OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in hu...OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.展开更多
Identification of carotid artery atherosclerosis is crucial for the diagnosis of the cerebral apoplexy and other vascular diseases.Intravascular optical tomography(IVOCT)has been employed to clinical coronary imaging ...Identification of carotid artery atherosclerosis is crucial for the diagnosis of the cerebral apoplexy and other vascular diseases.Intravascular optical tomography(IVOCT)has been employed to clinical coronary imaging for several years.Vessel morphological information on IVOCT images together with blood flow information on Doppler OCT(DOCT)images could provide a more accurate internal environment of arteries.Images integrated with fluid-structure interaction(FSI)could obtain the accurate mechanical responses and the quantitative material characters.A porcine carotid artery was imaged with an intravascular system(C7-XR,St.Jude Medical Inc.St.Paul,Minnesota,USA)in vivo,during which 120 images of one section and 600 images of a 5 mm/s pull back were captured within 6 s.Those images were then overlapped with Doppler phase changes to imply the changes in flow profiles.Segmentation and quantification of vessel structure was done in the software(MATLAB 2014b),including specifically the segmentation of lumen,imaging catheter,vessel wall and the guide wire.Appropriate interpolation functions are selected in the coordinate transformation algorithm to have smooth boundaries from images.A set of flow algorithms include image segmentation,three-dimensional/two-dimensional model reconstruction,inversion of material parameters,fitting of experimental velocity data and theoretical derivation based on simulation results is proposed.All steps are programmed to provide a theoretical basis for the future simplified process control.3D-reconstruction FSI model was built in SOLIDWORKS by lofting operation based on the segmentation results.Commercial finite element software(COMSOL 5.3,Sweden)numerically analyzed the entity model to obtain vessel stress/strain and flow shear stress data.Boundary conditions are from the OCT detection.Material of the artery was set to be the modified Mooney-Rivlin constitutive model and the parameters used were adjusted in an algorithm to match an ex vivo experiment.Wall shear stresses(WSS)and vessel deformations were chosen to measure the conditions of the artery and would serve as a target variables for future prediction.Thus,the geometric information together with the data of materials and other mechanical properties are possible to obtain during the imaging process.Segmentation process provided anatomically correct models of a two-layered artery.Numerical simulation permits reliable stress distribution in which the position of catheter and the artery curvature have a neglectable disturbance.Shear stress of the fluid is quite small compared with that of the wall at the same interface,which shows good agreement with the former studies.Moreover,a high flushing speed of 0.1 mps have little impact on the stress distributions and magnitudes,which denotes that the OCT imaging process brings little harm to the vessel.It is the first attempt to combine the OCT imaging and Doppler OCT within a full algorithm and a structural analysis.This study is helpful for the biomechanical property studies of carotid arteries and the development of medical imaging technology.展开更多
Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. In order to examine whether arsenic affects vasomotor tone in blood vessels, ...Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. In order to examine whether arsenic affects vasomotor tone in blood vessels, we investigated the effect of arsenic on agonist-induced vasorelaxation and vasoconstriction using the isolated rat aortic rings in in vitro organ bath system. Treatment with inorganic arsenite (AsⅢ) inhibited acetylcholine-induced relaxation of aortic rings by inhibiting production of nitric oxide in endothelium.展开更多
OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(...OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(CCVDs)remains not comprehensive understanding.Hence,a network pharmacology-based method was suggested in this study to address this problem.METHODS This study was based on network pharmacology and bioinformatics analysis.Information on compounds in herbal medicines of triphala formula was acquired from public databases.Oral bioavailability as well as drug-likeness were screened by using absorption,distribution,metabolism,and excretion(ADME)criteria.Then,components of triphala,candidate targets of each component and known therapeutic targets of CCVDs were collected.Compound-target gene and compounds-CCVDs target networks were created through network pharmacology data sources.In addition,key targets and pathway enrichment were analyzed by STRING database and DAVID database.Moreover,we verified three of the key targets(PTGS2,MMP9 and IL-6)predicted by using Western blotting analysis.RESULTS Network analysis determined 132 compounds in three herbal medicines that were subjected to ADME screening,and 23 compounds as well as 65 genes formed the principal pathways linked to CCVDs.And 10 compounds,which actually linked to more than three genes,are determined as crucial chemicals.Core genes in this network were IL-6,TNF,VEGFA,PTGS2,CXCL8,TP53,CCL2,IL-10,MMP9 and SERPINE1.And pathways in cancer,TNF signaling path⁃way,neuroactive ligand-receptor interaction,etc.related to CCVDs were identified.In vitro experiments,the results indi⁃cated that compared with the control group(no treatment),PTGS2,MMP9 and IL-6 were up-regulated by treatment of 10μg·L^-1 TNF-α,while pretreatment with 20-80 mg·L^-1 triphala could significantly inhibit the expression of PTGS2,MMP9 and IL-6.With increasing Triphala concentration,the expression of PTGS2,MMP9 and IL-6 decreased.CON⁃CLUSION Complex components and pharmacological mechanism of triphala,and obtained some potential therapeutic targets of CCVDs,which could provide theoretical basis for the research and development of new drugs for treating CCVDs.展开更多
OBJECTIVE Atherosclerosis(AS)is a chronic inflammatory disease characterized by the accumulation of lipids,vascular fibrosis,and inflammation.Paeonol(Pae)is a natural phenolic compounds isolated from a traditional Chi...OBJECTIVE Atherosclerosis(AS)is a chronic inflammatory disease characterized by the accumulation of lipids,vascular fibrosis,and inflammation.Paeonol(Pae)is a natural phenolic compounds isolated from a traditional Chinese medicine,Cortex Moutan,which exhibits anti-AS effects.Our previous work demonstrated that gut microbiota plays an important role during AS treatment as it affects the efficacy of Pae.However,the mechanism of Pae in protecting against vascular fibrosis as related to gut microbiota has yet to be elucidated.To investigate the anti-fibrosis effect of Pae on AS mice and demonstrate the underlying gut microbiota-dependent mechanism.METHODS ApoE-/-mice were fed with high-fat-diet(HFD)to replicate the AS model.HE and Masson staining were used to observe the plaque formation and collagen deposition.Gut microbiota alteration and short-chain fatty acids(SCFAs)production were analyzed through 16S rRNA sequencing and LC-MS/MS.The frequency of immune cells in spleen were phenotyped by flow cytometry.The mRNA expression of aortic inflammatory cytokines were detected by qRT-PCR.The protein expression of LOX and fibrosis related indicators were examined by Western blotting.RESULTS Pae restricted the development of AS and collagen deposition.Notably,the anti-fibrosis effect of Pae was achieved by regulating the gut microbiota.16S rRNA sequencing and LC-MS/MS data indicated that the relative abundance of SCFAs-producing bacteria and SCFAs production was increased.Additionally,Pae administration selectively up-regulated the frequency of regulatory T(Treg)cells as well as down-regulated the ratio of T helper type 17(Th17)cells in the spleen of AS mice,improving the Treg/Th17 balance.In addition,as expected,Pae intervention significantly down-regulate the mRNA expression levels of pro-inflammatory cytokines IL^(-1)β,IL-6,TNF-αand IL^(-1)7 in the aorta tissue,up-regulate the levels of anti-inflammatory factor IL^(-1)0,a marker of Treg cells.Finally,Pae′s intervention in the gut microbiota resulted in the restoration of the balance of Treg/Th17,which indirectly down-regulated the protein expression level of LOX and fibrosis-related indicators(MMP-2/9 and collagenⅠ/Ⅲ).CONCLUSION Pae attenuates vascular fibrosis in a gut microbiota-dependent manner.The underlying protective mechanism is associated with the improved Treg/Th17 balance in spleen mediated through the increased microbiota-derived SCFAs production.展开更多
It is well established in experimental animals and Humans that endothelial cells,which cover the luminal surface of all blood vessels,have a pivotal role in the control of vascular homeostasis.The protective effect of...It is well established in experimental animals and Humans that endothelial cells,which cover the luminal surface of all blood vessels,have a pivotal role in the control of vascular homeostasis.The protective effect of endothelial cells is mostly due to their ability to respond to circulating hormones,autacoids,blood-and platelet-derived factors,and also to blood flow by inducing potent vasoprotectivemechanismsincluding predominantlythe formation of nitric oxide(NO),and,often also to some extent,endothelium-derived hyperpolarization,and prostacyclin(PGI2).Besides being a potent vasodilator,NO also effectively prevents platelet activation and has anti-thrombotic and anti-atherosclerotic properties.An endothelial dysfunction characterized by a reduced generation of these endothelium-dependent vasodilator mechanisms associated with vascular oxidative stress and the formation of endothelium-derived contracting factors such as contractile prostanoids is often observed in most types of cardiovascular diseases including hypertension,hypercho⁃lesterolemia,diabetes,and also during physiological ageing in both experimental animals and Humans.Nutrition-derived polyphenols such as those from grapes,tea,cocoa,and berries have been shown to stimulate the endothelial formation of NO by activating the Src/PI3-kinase/Akt-dependent phosphorylation of endothelial NO synthase(eNOS)and to enhance eNOS expression.As a consequence,the active polyphenols will promote a sustained forma⁃tion of NO that contributes to protect the vascular system.Polyphenol-rich products have also been shown to improve an established endothelial dysfunction and to delay the onset of the induction of an endothelial dysfunction in several experimental models of cardiovascular diseases including hypertension and in ageing.Moreover,endothelial senescence characterized by cell cycle arrest and the acquisition of a pro-inflammatory and pro-atherothrombotic phenotype has been identified as an early event promotingthe development of endothelial dysfunc⁃tion.Premature endothelial senescence appears to affect,in particular,arterial sites at risk such as curvatures and bifur⁃cations that are characterized by disturbed flow and low shear stress.The pro-senescent process can be further increased in the presence of a high concentration of glucose,oxidized LDL,and angiotensinⅡ.Anthocyanin-rich products have been shown to accumulate preferentially in senescent endothelial cells,to reduce the expression of cell cycle regulators such as p16,p21 and p53,and to improve the endothelial function.The protective effect is mostly due to their ability to reduce vascular oxidative stress by inhibiting the overexpression of NADPH oxidase and the local angiotensin system.Thus,nutrition-derived polyphenols may be an interesting approach to delay the onset of risk factor-and ageing-related endothelial senescence and dysfunction and,hence,to promote vascular health.展开更多
OBJECTIVE To systematically review the clinical efficacy and safety on TCHMs that are used for vascular dementia(VaD).METHODS To identify studies for systematical review,electronic searches were performed through seve...OBJECTIVE To systematically review the clinical efficacy and safety on TCHMs that are used for vascular dementia(VaD).METHODS To identify studies for systematical review,electronic searches were performed through several databases-ALOIS,CNKI,CBM,Weipu,Wanfang,etc.Only randomized control trials(RCTs)or controlled clinical trials(CCTs)were included.Patients were diagnosed with VaD by diagnostic criteria(DSM,NINDS-AIREN,ICD or HIS)as well as imaging technique(CT,MRI or functional imaging,etc).Eligible TCHMs must be recognized in the Chinese Pharmacopeia or the National Essential Drug List of the People′s Republic of China.Included studies were appraised using the Cochrane Collaboration risk-of-bias criteria.Efficacy and safety outcomes were evaluated by meta-analysis.Efficacy outcomes include cognition,daily function,global performance and behaviour;safety was assessed by the number of adverse events and number of subjects experiencing adverse events.Assessment of heterogeneity,subgroup analysis and sensitivity analysis were also performed.RESULTS A total of 46 trials on 29TCHMs(3522patients)were included.45 studies were RCTs and 1was CCT.In these 45 RCTs,only 2were appraised as adequately randomised.5of 46 trials were appraised as having low risk of bias in blinding.Sample sizes were generally small ranging from 26 to 216with a median of 68.All trials were conducted in China from 1997 to 2013.All 46 studies assessed cognition using one or a combination of the following scales:MMSE(n=40 studies;3096 patients),HDS(n=22;1664 patients),ADAS-Cog(n=4;241 patients),CDT(n=1;60patients)and CCSE(n=1;26patients).Half of the studies assessed daily function using either the ADL(n=22;1743 patients)or IADL(n=2;203patients).Only 6studies measured behaviour using the FAQ(n=3;226 subjects),BBS(n=1;48patients),NPI(n=1;100subjects)or Neurological Deficits Function Scale(n=1;91patients).30 studies measured global performance.31 of 46 studies made conclusions regarding the safety of the TCHMs.Despite the problems of methodology and reporting,we can identify three TCHMs-NaoXinTong,Shenfu and Tongxinluo as having relatively stronger evidence of efficacy.There is weak evidence for the safety of TCHMs for VaD.CONCLUSION There is weak evidence for the efficacy and safety of TCHMs for VaD because of the poor methodology,short duration of follow-up and inadequate reporting.However the agents appear to be relatively free of severe short-term AEs,hence we encourage further better designed and reported trials.展开更多
OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether s...OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether salvianolic acid A(SAA)extracted from the traditional Chinese medicine′Dan Shen′attenuated vascular remodeling in a PAH rat model,and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg-1,sc).The rats were orally treated with either SAA(0.3,1,3 mg·kg-1·d-1)or a positive control bosentan(30 mg·kg-1·d-1)for 4 weeks.Echocardiography and hemodynamic measurements were performed on d 28.Then the hearts and lungs were harvested,the organ indices and pulmonary artery wall thickness were calculated,and biochemical and histochemical analysis were conducted.The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting.RESULTS Treatment with SAA or bosentan effectively ameliorated MCTinduced pulmonary artery remodeling,pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal injury and collagen deposition in the lungs.Moreover,the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs.The treatments partially restored MCT-induced reductions of bone morphogenetic protein typeⅡreceptor(BMPRⅡ)and phosphorylated Smad1/5 in the lungs.CONCLUSION SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRⅡ-Smad pathway and inhibiting apoptosis.Thus,SAA may have therapeutic potential for the patients at high risk of PAH.展开更多
OBJECTIVE To investigate the role of adventitial vasa vasorum in artery remodeling during the process of pulmonary artery hypertension(PAH),we checked the small heat shock protein 27/25(HSPB1)whether involved in patho...OBJECTIVE To investigate the role of adventitial vasa vasorum in artery remodeling during the process of pulmonary artery hypertension(PAH),we checked the small heat shock protein 27/25(HSPB1)whether involved in pathological basis of vascular remodeling.METHODS We explored the potential role of HSPB1 interacts with ectopic F1Fo-ATPase in the pulmonary vascular remodeling,investigate its effects on the endothelium cell dynamic,and further reveal its possible molecular mechanisms using hypoxic pulmonary hypertension rat model,transgenic mice and pulmonary adventitial vasa vasorum endothelial cell culture in vitro.RESULTS Our studies have shown that HSPB1 improves adventitial vasa vasorum angiogenesis and remodeling.We found that hypoxia induces-HSPB1 upregulation and HSPB1 interact with ectopic F1Fo-ATPase modulate adventitial vasa vasorum endothelial cell proliferation,migration and tube formation.And the inhibition of HSPB1can reverse the vascular inflammation and fibrosis amazingly.CONCLUSION Adventitial vasa vasorum plays an important role in vascular remodeling,and small heat shock protein 27/25 was involved in a variety of diseases during the development of PAH,which could an efficient therapeutic targets and prevention strategy for PAH clinical.展开更多
Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described...Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described as converting from a contractile state into a synthetic phenotype,is a crucial event during vascular remodeling.Recently,micro RNAs(mi RNAs)a kind of small non-coding RNA molecules,has been proven to target critical genes of cell signaling pathways to regulate SMC phenotypic change.By searching the Pub Med,Embase,reviews,and reference listsof relevant papers,we systematically carried out a review of the literature to provide an overview of the mi RNAs and their target genes in cell signaling pathways,focus inthe pathways involving in SMC phenotype change.To be specific,mi RNAs that regulate genes involved in the MAPK signaling pathways(such as:mi R-155,mi R-92a,mi R-424/503,mi R-133,mi R-181b,mi R-31,mi R-1298,mi R-132,mi R-200c and mi R-483-3p),mi RNAs target genes involved in the TGF-βsignaling pathways(including mi R-24,mi R-17/92 cluster,mi R-599,mi R-21 and mi R-143/145),mi RNAs target the genes involved in the AMPK signaling pathways including mi R-144/451 and mi R-195,mi RNAs target the genes involved in the PI3K-Akt signaling pathways(including mi R-138,mi R-34c,mi R-223,mi R-761,mi R-10a,mi R-146a),mi R-199a-5ptargets the genes involved in the Wnt signaling pathways mi RNAs(mi R-221/222,mi R-15b,mi R-24/29a,mi R-224)involved in the PDGF signaling pathways and some mi RNAs(mi R-638,mi R-328,mi R-365,mi R-663,mi R-29b,mi R-130,mi R-142-5p,mi R-424/322)which regulate SMC phenotype change by other corresponding targets were in detailed discussed in our review.Exploring the regulation of miR NAs in key cellsignaling pathways-mediatedvascular remodeling wil have momentous impact on identifying novel therapeutic targets for its associated disease.展开更多
OBJECTIVE To explore the role of calpain in in pulmonary vascular remodeling in hypoxia induced pulmonary hypertension and the underlying mechanism.METHODS Sprague-Dawley rats were randomly divided into hypoxia group ...OBJECTIVE To explore the role of calpain in in pulmonary vascular remodeling in hypoxia induced pulmonary hypertension and the underlying mechanism.METHODS Sprague-Dawley rats were randomly divided into hypoxia group and normoxia control group.Right ventricular systolic pressure(RVSP)and mean pulmonary artery pressure(m PAP)were monitored by the method of right external jugular vein cannula.Right ventricular hypertrophy index was expressed as the ratio of right ventricular weight to left ventricular weight(left ventricle plus septum weight).Level of calpain-1,calpain-2and calpain-4 m RNA in pulmonary artery trunk were determined by real-time PCR.Expression of calpain-1,calpain-2 and calpain-4 protein was determined by Western Blot.Primary rat pulmonary arterial smooth muscle cells(PASMCs)were divided into 4 groups:normoxia control group,normoxia+MDL28170 group,hypoxia group and hypoxia+MDL28170 group.Cell proliferation was detected by MTS and flow cytometry.Level of Ki-67 and PCNA m RNA were determined by real-time PCR.RESULTS RVSP,m PAP and right ventricular remodeling index were significantly higher in the hypoxia group than those in the normoxia group.In the hypoxia group,pulmonary vascular remodeling occurred,and the expression of calpain-1,calpain-2 and calpain-4 m RNA and protein expression was increased in the pulmonary artery.MDL28170 significantly inhibited hypoxia-induced proliferation of PASMCs accompanied with decreased Ki-67and PCNA m RNA expression.CONCLUSION Calpain mediated vascular remodeling via promoting proliferation of PASMCs in hypoxia induced pulmonary hypertension.展开更多
Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodelin...Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodeling is abnormal variations of vascular cell phenotype,morphological structure and functions such as migration,hypertrophy,proliferation and apoptosis.Numerous researches revealed that mechanical stress,including shear stress and cyclic stretch,participates in physiological vascular homeostasis,or pathophysiological vascular remodeling.The understanding of mechanobiological mechanism in vascular remodeling will play a unique role in understanding human physiology and disease,and will generate important theoretical and clinical significance [2].Non-coding RNAs are newly recognized RNAs which cannot be translated into proteins but are involved in epigenetic modification of gene regulation.The studies revealed that non-coding RNAs,such as microRNAs(miRNAs)and long noncoding RNAs(long ncRNAs,IncRNA),as well as small interfering RNAs(siRNAs),piwi-interacting RNAs(piRNAs),small nucleolar RNAs(snoRNAs),play essential roles in the regulation of various processes,such as metabolism,development,cell proliferation,cell apoptosis,cell differentiation,oncogenesis and vascular homeostasis[5].However,the roles of non-coding RNAs in the cardiovascular system under mechanical stresses are still not clarified.Our recent researches detected the mechanical regulation of IncRNAs and miRNAs in vascular remodeling.LncRNAs are non-protein-coding transcripts that are longer than 200 nucleotides(nt),which is an arbitrary cut-off value that distinguishes these transcripts from other small RNAs.Unlike the well-established mechanism of microRNA action,the functional mode of IncRNAs is not fully understood.Increasing evidence shows that IncRNAs modulate gene expression via a multilevel-regulated pathway.Given their large number and complicated functional modes,lncRNAs are emerging as important regulators of a variety of cellular responses,developmental processes and diseases.Using a gene microarray,we screened the differences in the IncRNAs and mRNAs between spontaneously hypertensive rats(SHR)and Wistar Kyoto rats(WKY).The results showed that 68 IncRNAs and 255 mRNAs were up-regulated in the aorta of SHR,while 167 IncRNAs and 272 mRNAs were down-regulated.Expressions of the screened IncRNAs,including XR007793,were validated by real-time PCR.A co-expression network was composed,and gene function was analysed using Ingenuity Pathway Analysis.In vitro,vascular smooth muscle cells(VSMCs)were subjected to cyclic stretch at a magnitude of 5%(physiological normotensive cyclic stretch)or 15%(pathological hypertensive cyclic stretch)by Flexercell-5000TM.15%-cyclic-stretch increased XR007793 expression.XR007793 knockdown attenuated VSMC proliferation and migration and inhibited co-expressed genes such as signal transducers and activators of transcription 2(stat2),LIM domain only 2(lmo2)and interferon regulatory factor 7(irf7)[4].Illuminating the role of IncRNAs in vascular remodeling induced by hyper mechanical stretch may provide deeper insight into the mechanobiological mechanism underlying hypertension,and contribute to identifying potential targets for hypertension therapy.miRNAs are endogenous,non-coding,single-stranded RNAs of 18-22 nucleotides that constitute a novel class of gene regulators.miRNAs bind to their target genes within their 3’-untranslated regions(3’-UTRs),leading to direct degradation of mRNA or translational repression by a complete,i.e.in plants,or incomplete,i.e.in animals,complement respectively.Our resent works revealed several important mechano-responsive miRNA and their potential effects in vascular remodeling.Forexample,miRNA-33 is regulated by cyclic stretch in the grafted vessels,which targets to BMP3 and subsequent modulates smad signaling pathway.The miRNA-33-BMP3-smad pathway protects against venous VSMC proliferation in response to arterial cyclic stretch.Therefore,miRNA-33 may be a potential therapeutic target in autologous vein grafted surgery,and locally overexpression of miR-33 may attenuates neointimal hyperplasia of grafted human saphenous vein [3].The unpublished data revealed that 15%cyclic stretch also significantly elevated the expression of miRNA-124-3p which bound to the 3’UTR of Lmna mRNA,and then negatively regulated protein expression of lamin A/C which is the important skeletal proteins in nucleus.In addition to primary intracellular locations of miRNAs,our recent study showed that miRNAs can be secreted and protected extracellularly via inclusion into membrane-derived vesicles including microparticles.Microparticles are extracellular vesicles ranging from 0.1 to 1μm in size and have been shown to deliver various bioactive molecules,i.e.,chemokines,enzymes and miRNAs,to recipient cells.Increasing evidence shows that microparticles play a pivotal role in many pathological processes,such as cancer,inflammatory diseases and cardiovascular disease.Our present study showed that platelet-derived microparticles(PMPs),which are released by active platelets,are important vehicles for communication and play crucial roles in inducing abnormal EC proliferation in hypertension.In briefly,EC proliferation was increased in renal hypertensive rats established by abdominal aortic coarctation compared to control rats and that elevated thrombin in plasma promoted platelet activation,which may induce the release of PMPs.miRNA array and qPCR revealed a higher level of miRNA-142-3p in platelets and PMPs.In vitro,PMPs delivered miRNA-142-3p into ECs and enhanced EC proliferation via Bcl-2-associated transcription factor 1(BCLAF1)and its downstream genes.These results indicated that PMPs deliver miRNA-142-3p from activated platelets into ECs and that miRNA-142-3p may play important roles in EC dysfunction under hypertensive conditions and might be a novel therapeutic target for maintaining EC homeostasis in hypertension[1].These results provide possible mechanisms by which non-coding RNAs regulate cellular functions under different mechanical stresses,and suggest a novel potential therapeutic approach for vascular remodeling.The further studies on noncoding RNAs may provide new insight into understanding the mechanism of vascular remodeling in different various cardiovascular disorders,and may provide novel targets for the maintenance of vascular homeostasis.展开更多
Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,h...Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,heart,lung,and peripheral vasculatures. Pathological vascular remodeling occurs in response to a variety of vascular insults such as mechanical(angioplasty or stenting) or biological(lipids,diabetes,smoking,or virus) injuries. It is a polygenic process involving multiple cell types in the vessel wall or circulation,including endothelial cells(ECs),smooth muscle cells(SMCs),fibroblasts,leukocytes,and platelets. One of hallmarks is the transition of vascular smooth muscle cells(SMCs)from a differentiated/quiescent contractile phenotype to a myofibroblast-like dedifferentiated/active so-called synthetic phenotype. Synthetic SMCs are proliferatory,migratory,secretory and inflammatory,playing key roles in the pathogenesis of vascular remodeling. In the normal vessel,ECs synthesize and secrete biological substances such as prostacyclins(PGI_2) and nitric oxide(NO) that not only function as vasodilators but also inhibit SMC phenotype transition and other properties associated with the synthetic phenotype. Cyclic nucleotides cAMP and cGMP are primary mediators of PGI_2 and NO,respectively,and play critical roles in control vascular structural integrity and function. Cyclic nucleotides are controlled by selective activation or inhibition of distinct cyclic nucleotide phosphodiesterase(PDE) isozymes catalyzing the degradation reaction. To date,more than 60 different PDE isoenzymes derived from 22 genes are identified and grouped into 11 broad families(PDE1-PDE11). PDEs are expressed in a cell/tissue-specific manner and only a few enzymes are expressed in any single cell type. Through systematic assessment of the expression levels of all known PDE isoforms in contractile versus synthetic SMCs,we found that the expression levels of a number of PDE are significantly altered between two SMC phenotypes. We then explored the functional roles and underlying mechanisms of these altered PDEs in vascular SMCs pathogenesis and vascular remodeling in vitro and in vivo using a variety of gain-of-or loss-of-function approaches. For example,we found that Ca^(2+)/calmodulinstimulated cAMP/cGMP-hydrolyzing PDE 1C is selectively expressed in synthetic SMCs in vitro and in various vascular disease models in vivo. PDE 1C upregulation contributes to a number of pathogenic functions of synthetic SMCs,such as cell proliferation,migration,and matrix protein metabolism.PDE 1C deficiency markedly attenuates intimal hyperplasia,atherosclerosis,and aortic aneurysm in experimental mouse disease models. These findings suggest that PDE 1C functions as a key regulator of the synthetic SMC pathology in vascular remodeling. Inhibiting PDE 1C function may represent a novel therapeutic strategy for protecting against the pathogenesis of vascular diseases.展开更多
Mechanobiology is the study of how stress and strain are generated by cells and how these mechanical factors regulate cell morphology and function.The vascular system is subject to tensile and compressive stress and s...Mechanobiology is the study of how stress and strain are generated by cells and how these mechanical factors regulate cell morphology and function.The vascular system is subject to tensile and compressive stress and strain in the blood vessel wal that are generated by blood pressure and play a pivotal role in regulating vascular cell activities including proliferation,differentiation,apoptosis,and migration.These cellular processes are essential to vascular development,performance,and pathogenic alterations.Dr.Y.C.Fung has made significant contributions to vascular mechanobiology—establishing the uniform stress theory,addressing the generation and significance of uniform stress and strain across the blood vessel wall,and proposing the stress-growth theory,addressing the role of mechanical stress in regulating cell proliferative ac-tivities(Fung 1984,Fung 1990).These theories have exerted a profound impact on the development of Biomechanics and Mechanobiology in the vascular as well as other systems.展开更多
Objective The apoptosis of vascular smooth muscle cells(VSMCs)influenced by abnormal cyclic stretch is crucial for vascular remodeling during hypertension.We explored that the causes of mechano-responsive lamin A/C ch...Objective The apoptosis of vascular smooth muscle cells(VSMCs)influenced by abnormal cyclic stretch is crucial for vascular remodeling during hypertension.We explored that the causes of mechano-responsive lamin A/C changingin aonormai cyclic stretcn and its roles in VSMC apoptosis.Methods and results Our previous vascular proteomics study revealed that LaminA/C is mechano-sensitive molecule.When VSMCs are subjected to cyclic stretch,the expression of LaminA/C is significantly changed which participates dysfunctions of VSMCs during hypertension.However,the molecular mechanism involved in regulation of LaminA/C expression and the role of LaminA/C in the VSMC apoptosis during cyclic stretch application are still unclear.In the present study,VSMCs were subjected to different amplitudes of cyclic steetch in vitro:5%cyclic stretch(physiological strain)or 15%cyclic stretch(pathological strain).The expression of 2 different selective cleavage isomers of LaminA/C,i.e.LaminA and LaminC,and the apoptosis of VSMCs were detected.The results showed that compared with 5%group,15%cyclic stretch significantly decreased the expression of LaminA and LaminC,and promoted the apoptosis of VSMCs.Using specific small interfering RNA(siRNA)transfection which targets on LMNA the encoding gene of LaminA/C,the expression of LaminA and LaminC in VSMCs was significantly decreased,and the apoptosis was significantly increased.In order to study the molecular mechanism involved in cyclic stretch regulating the expression of LaminA/C,we focused on the microRNA(miR).Bioinformatics analysis showed that the 3’untranslated region(3’UTR)of LMNA has two potential binding sites to miR-124-3p.Double luciferase reported system revealed that both sites have binding abilities to miR-124-3p.Under static condition,miR-124-3p inhibitor significantly up-regulated the expression levels of LaminA and LaminC,while the miR-124-3p mimics significantly down-regulated them.RT-PCR results showed that 15%cyclic stretch significantly up-regulated the expression of miR-124-3p compared with 5%cyclic stretch.Furthermore,in order to study the role of changeed LaminA/C in VSMC apoptosis,LMNA-specific siRNA was transfected to repress the expression of LaminA/C in VSMCs,and Protein/DNA microarray was used to detecte the activity of transcription factors.The transcription factors whose activity were changed significantly(increase or decrease more than 2 times)were analyzed by cluster analysis and ingenurity pathway analysis(IPA).Six transcription factors associated with apoptosis were screened,in which TP53 was activated by the specific siRNA transfection and the other 5 were inavtived,including TP53,CREB1,MYC,STAT1/5/6 and JUN.Using abdominal aorta coarctation hypertensive model,the change of miR-124-3p in VSMCs was explored in vivo.A marked increase of miR-124-3p in thoracic aorta was revealed compared with the sham-operated controls,and in situ FISH revealed that this increase was mainly in the VSMCs.Conclusions The present study suggest that abnormally increased cyclic stretch(15%)up-regulates the expression of miR-124-3p in VSMCs,which subsequently targets on the 3’UTR of LMNA and decreases the expression of nuclear envelope protein LaminA/C;the repressed LaminA/C may play an important role in the apoptosis of VSMCs by regulating the activity of virious transcription factors,such as TP53,CREB1,MYC,STAT1/5/6 and JUN.The present study may provide a new insight into understanding the molecular mechanisms of vascular remodeling.展开更多
Aim Angiotensin II （AngII） induces vascular smooth muscle cell （VSMC） migration and growth, which is responsible for vascular remodeling during some cardiovascular diseases. It has been demonstrated to activate a ...Aim Angiotensin II （AngII） induces vascular smooth muscle cell （VSMC） migration and growth, which is responsible for vascular remodeling during some cardiovascular diseases. It has been demonstrated to activate a C1 current, but the underlying mechanism is not clear. Methods Whole-cell patch clamp, co-immunoprecipitation （co-IP）, site-specific mutagenesis, angiotensinII-infusion hypertensive mice model were used. Results In VSMCs, AngII could induce a C1C-3-dependent C1- current that was abolished in C1C-3 null mice. The activation mechanism of this AngII-induced C1- current was ascribed to the interaction between C1C-3 and Rho-kinase 2 （ROCIL2）, as re- vealed by N-terminal or C-terminal truncation of C1C-3, ROCIC2 siRNA and Co-IP experiments. Then we searched for and identified the phosphorylation site of C1C-3 at threonine 532 is critical for AngII-induced C1- current and VSMC migration through ROCK. The C1C-3 T532D mutant （mutation of threonine 532 to aspartate）, mimicking the phos- phorylation state of C1C-3, significantly potentiated AngII-induced C1- current and VSMC migration; while C1C-3 T532A （mutation of threonine 532 to alanine） had the opposite effects. Furthermore, we found a remarkably de- creased AngII-induced VSMC migration in C1C-3 null mice that is insensitive to Y27632, an inhibitor of ROCIL2. In addition, AngII-induced cerebrovascular remodeling was ameliorated in C1C-3 null mice, possibly by ROCIL2 path- way. Conclusions C1C-3 protein phosphorylation at threonine 532 by ROCIL2 is required for AngII-induced C1- cur- rent and VSMC migration that are involved in AngII-induced hypertensive vascular remodeling.展开更多
Aim Alpha7 nicotinic acetylcholine receptor （α7nAChR）, a subtype of nAChR regulating neurotrans- mission in central nervous system, is an essential regulator of cholinergic antiinflammatory pathway in periphery. Th...Aim Alpha7 nicotinic acetylcholine receptor （α7nAChR）, a subtype of nAChR regulating neurotrans- mission in central nervous system, is an essential regulator of cholinergic antiinflammatory pathway in periphery. The present study was to determine the effects of activation of α7nAChR on oxidant stress-induced injury in endo- thelial cells. Methods Cultured human umbilical vein endothelial cells were treated with H202 （400 μmol · L^-1） or H202plus PNU-282987 （ 10 μmol · L^-1 ）. Cell viability and membrane integrity were measured. AnnexinV ＋ PI assay, immunoblotting of bcl-2, bax and cleaved caspase-3, and immunofluorescence of apoptosis inducing factor （AIF） were performed to evaluate apoptosis. Protein expression of vascular peroxidase-1 （ VPO-1 ） and phosphor- JNK were measured by immunoblotting. Results Activation of α7nAChR by a selective agonist PNU-282987 pre-vented H202-indced decrease of cell viability and increase of lactate dehydrogenase release. Activation of α7nAChR markedly reduced cell apoptosis and intracellular oxidative stress level. Moreover, activation of α7nAChR reduced H2 02 -induced VPO-1 protein upregulation and JNK1/2 phosphorylation. The inhibitory effect of α7nAChR activa- tion on VPO-1 was blocked by JNK inhibitor SP600125. In addition, pretreatment of α7nAChR antagonist methyl- lycaconitine blocked the cytoprotective effect of PNU-282987. Conclusion These results provide the first evidence that activation of α7nAChR protects against oxidant stress-induced damage by suppressing VPO-1 in a JNK signa- ling pathway-dependent manner in endothelial cells.展开更多
OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with wh...OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with white matter damage,and optogenetics and skin stroking were exerted to activate glutamater⁃gic neurons in the somatosensory cortex in a clas⁃sical mouse model of ischemia vascular dementia.RESULTS White matter damage was correlated with disrupted cortical structure from MRI results.In a mouse model,activating glutamatergic neu⁃rons in the somatosensory cortex promotes prolif⁃eration of OPCs and remyelination to rescue cog⁃nitive impairment after chronic cerebral hypoper⁃fusion.Such therapeutic action was limited to stimulation with moderate intensity at the upper layers of the cortex,but was achieved over a wide time window after ischemia.Mechanistically,enhanced glutamatergic neuron-OPC functional synaptic connections are required for protection from activation of cortical glutamatergic neurons.Finally,skin stroking activation of the somatosen⁃sory cortex,an easier approach for clinical trans⁃lation,promoted OPC proliferation and remyelin⁃ation as well as cognitive recovery after cerebral hypoperfusion.CONCLUSION Activation of gluta⁃matergic neurons in the somatosensory cortex may serve as novel approaches for treating isch⁃emic vascular dementia through precise modula⁃tion of glutamatergic neuron-OPC circuits.展开更多
Background and Objective In-stent restenosis(ISR)remains a major limitation of percutaneous coronary intervention despite improvements in stent design and pharmacological agents,whereas the mechanism of ISR has not be...Background and Objective In-stent restenosis(ISR)remains a major limitation of percutaneous coronary intervention despite improvements in stent design and pharmacological agents,whereas the mechanism of ISR has not been fully clarified.In the present study,we sought to investigate the potential association of serum soluble TREM-1(sTREM-1)levels with the incidence of ISR.The role of TREM-1 was evaluated in cultured vascular smooth muscle cells(VSMCs).展开更多
Instruction Shear stress,caused by the parallel frictional drag force of blood flow,is a biomechanical force which plays an important role in the control of blood vessels growth and functions [1]. Clinical researches ...Instruction Shear stress,caused by the parallel frictional drag force of blood flow,is a biomechanical force which plays an important role in the control of blood vessels growth and functions [1]. Clinical researches had found out that atherosclerotic le-展开更多
基金supported by National Science Foundation of China(81402943)CAMS Major Collaborative Innovation Project(2016-I2M-1-011)PUMC Youth Fund(3332015168)
文摘OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.
基金supported by the National Natural Science Foundation of China ( 11602166)the Natural Science Foundation of Tianjin ( Grant 16JCYBJC40500)the Key Projects in the Tianjin Science & Technology Pillar Program ( 18YFZCSY00900)
文摘Identification of carotid artery atherosclerosis is crucial for the diagnosis of the cerebral apoplexy and other vascular diseases.Intravascular optical tomography(IVOCT)has been employed to clinical coronary imaging for several years.Vessel morphological information on IVOCT images together with blood flow information on Doppler OCT(DOCT)images could provide a more accurate internal environment of arteries.Images integrated with fluid-structure interaction(FSI)could obtain the accurate mechanical responses and the quantitative material characters.A porcine carotid artery was imaged with an intravascular system(C7-XR,St.Jude Medical Inc.St.Paul,Minnesota,USA)in vivo,during which 120 images of one section and 600 images of a 5 mm/s pull back were captured within 6 s.Those images were then overlapped with Doppler phase changes to imply the changes in flow profiles.Segmentation and quantification of vessel structure was done in the software(MATLAB 2014b),including specifically the segmentation of lumen,imaging catheter,vessel wall and the guide wire.Appropriate interpolation functions are selected in the coordinate transformation algorithm to have smooth boundaries from images.A set of flow algorithms include image segmentation,three-dimensional/two-dimensional model reconstruction,inversion of material parameters,fitting of experimental velocity data and theoretical derivation based on simulation results is proposed.All steps are programmed to provide a theoretical basis for the future simplified process control.3D-reconstruction FSI model was built in SOLIDWORKS by lofting operation based on the segmentation results.Commercial finite element software(COMSOL 5.3,Sweden)numerically analyzed the entity model to obtain vessel stress/strain and flow shear stress data.Boundary conditions are from the OCT detection.Material of the artery was set to be the modified Mooney-Rivlin constitutive model and the parameters used were adjusted in an algorithm to match an ex vivo experiment.Wall shear stresses(WSS)and vessel deformations were chosen to measure the conditions of the artery and would serve as a target variables for future prediction.Thus,the geometric information together with the data of materials and other mechanical properties are possible to obtain during the imaging process.Segmentation process provided anatomically correct models of a two-layered artery.Numerical simulation permits reliable stress distribution in which the position of catheter and the artery curvature have a neglectable disturbance.Shear stress of the fluid is quite small compared with that of the wall at the same interface,which shows good agreement with the former studies.Moreover,a high flushing speed of 0.1 mps have little impact on the stress distributions and magnitudes,which denotes that the OCT imaging process brings little harm to the vessel.It is the first attempt to combine the OCT imaging and Doppler OCT within a full algorithm and a structural analysis.This study is helpful for the biomechanical property studies of carotid arteries and the development of medical imaging technology.
文摘Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. In order to examine whether arsenic affects vasomotor tone in blood vessels, we investigated the effect of arsenic on agonist-induced vasorelaxation and vasoconstriction using the isolated rat aortic rings in in vitro organ bath system. Treatment with inorganic arsenite (AsⅢ) inhibited acetylcholine-induced relaxation of aortic rings by inhibiting production of nitric oxide in endothelium.
基金National Natural Science Foundation of China(81603385)China Postdoctoral Science Foundation(2018M643843)+1 种基金Natural Science Foundation of Shaanxi Province(2017JM8056)Key Research and Development Foundation of Shaanxi province(2018SF-241)
文摘OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(CCVDs)remains not comprehensive understanding.Hence,a network pharmacology-based method was suggested in this study to address this problem.METHODS This study was based on network pharmacology and bioinformatics analysis.Information on compounds in herbal medicines of triphala formula was acquired from public databases.Oral bioavailability as well as drug-likeness were screened by using absorption,distribution,metabolism,and excretion(ADME)criteria.Then,components of triphala,candidate targets of each component and known therapeutic targets of CCVDs were collected.Compound-target gene and compounds-CCVDs target networks were created through network pharmacology data sources.In addition,key targets and pathway enrichment were analyzed by STRING database and DAVID database.Moreover,we verified three of the key targets(PTGS2,MMP9 and IL-6)predicted by using Western blotting analysis.RESULTS Network analysis determined 132 compounds in three herbal medicines that were subjected to ADME screening,and 23 compounds as well as 65 genes formed the principal pathways linked to CCVDs.And 10 compounds,which actually linked to more than three genes,are determined as crucial chemicals.Core genes in this network were IL-6,TNF,VEGFA,PTGS2,CXCL8,TP53,CCL2,IL-10,MMP9 and SERPINE1.And pathways in cancer,TNF signaling path⁃way,neuroactive ligand-receptor interaction,etc.related to CCVDs were identified.In vitro experiments,the results indi⁃cated that compared with the control group(no treatment),PTGS2,MMP9 and IL-6 were up-regulated by treatment of 10μg·L^-1 TNF-α,while pretreatment with 20-80 mg·L^-1 triphala could significantly inhibit the expression of PTGS2,MMP9 and IL-6.With increasing Triphala concentration,the expression of PTGS2,MMP9 and IL-6 decreased.CON⁃CLUSION Complex components and pharmacological mechanism of triphala,and obtained some potential therapeutic targets of CCVDs,which could provide theoretical basis for the research and development of new drugs for treating CCVDs.
基金National Natural Science Foundation of China(81773937)。
文摘OBJECTIVE Atherosclerosis(AS)is a chronic inflammatory disease characterized by the accumulation of lipids,vascular fibrosis,and inflammation.Paeonol(Pae)is a natural phenolic compounds isolated from a traditional Chinese medicine,Cortex Moutan,which exhibits anti-AS effects.Our previous work demonstrated that gut microbiota plays an important role during AS treatment as it affects the efficacy of Pae.However,the mechanism of Pae in protecting against vascular fibrosis as related to gut microbiota has yet to be elucidated.To investigate the anti-fibrosis effect of Pae on AS mice and demonstrate the underlying gut microbiota-dependent mechanism.METHODS ApoE-/-mice were fed with high-fat-diet(HFD)to replicate the AS model.HE and Masson staining were used to observe the plaque formation and collagen deposition.Gut microbiota alteration and short-chain fatty acids(SCFAs)production were analyzed through 16S rRNA sequencing and LC-MS/MS.The frequency of immune cells in spleen were phenotyped by flow cytometry.The mRNA expression of aortic inflammatory cytokines were detected by qRT-PCR.The protein expression of LOX and fibrosis related indicators were examined by Western blotting.RESULTS Pae restricted the development of AS and collagen deposition.Notably,the anti-fibrosis effect of Pae was achieved by regulating the gut microbiota.16S rRNA sequencing and LC-MS/MS data indicated that the relative abundance of SCFAs-producing bacteria and SCFAs production was increased.Additionally,Pae administration selectively up-regulated the frequency of regulatory T(Treg)cells as well as down-regulated the ratio of T helper type 17(Th17)cells in the spleen of AS mice,improving the Treg/Th17 balance.In addition,as expected,Pae intervention significantly down-regulate the mRNA expression levels of pro-inflammatory cytokines IL^(-1)β,IL-6,TNF-αand IL^(-1)7 in the aorta tissue,up-regulate the levels of anti-inflammatory factor IL^(-1)0,a marker of Treg cells.Finally,Pae′s intervention in the gut microbiota resulted in the restoration of the balance of Treg/Th17,which indirectly down-regulated the protein expression level of LOX and fibrosis-related indicators(MMP-2/9 and collagenⅠ/Ⅲ).CONCLUSION Pae attenuates vascular fibrosis in a gut microbiota-dependent manner.The underlying protective mechanism is associated with the improved Treg/Th17 balance in spleen mediated through the increased microbiota-derived SCFAs production.
文摘It is well established in experimental animals and Humans that endothelial cells,which cover the luminal surface of all blood vessels,have a pivotal role in the control of vascular homeostasis.The protective effect of endothelial cells is mostly due to their ability to respond to circulating hormones,autacoids,blood-and platelet-derived factors,and also to blood flow by inducing potent vasoprotectivemechanismsincluding predominantlythe formation of nitric oxide(NO),and,often also to some extent,endothelium-derived hyperpolarization,and prostacyclin(PGI2).Besides being a potent vasodilator,NO also effectively prevents platelet activation and has anti-thrombotic and anti-atherosclerotic properties.An endothelial dysfunction characterized by a reduced generation of these endothelium-dependent vasodilator mechanisms associated with vascular oxidative stress and the formation of endothelium-derived contracting factors such as contractile prostanoids is often observed in most types of cardiovascular diseases including hypertension,hypercho⁃lesterolemia,diabetes,and also during physiological ageing in both experimental animals and Humans.Nutrition-derived polyphenols such as those from grapes,tea,cocoa,and berries have been shown to stimulate the endothelial formation of NO by activating the Src/PI3-kinase/Akt-dependent phosphorylation of endothelial NO synthase(eNOS)and to enhance eNOS expression.As a consequence,the active polyphenols will promote a sustained forma⁃tion of NO that contributes to protect the vascular system.Polyphenol-rich products have also been shown to improve an established endothelial dysfunction and to delay the onset of the induction of an endothelial dysfunction in several experimental models of cardiovascular diseases including hypertension and in ageing.Moreover,endothelial senescence characterized by cell cycle arrest and the acquisition of a pro-inflammatory and pro-atherothrombotic phenotype has been identified as an early event promotingthe development of endothelial dysfunc⁃tion.Premature endothelial senescence appears to affect,in particular,arterial sites at risk such as curvatures and bifur⁃cations that are characterized by disturbed flow and low shear stress.The pro-senescent process can be further increased in the presence of a high concentration of glucose,oxidized LDL,and angiotensinⅡ.Anthocyanin-rich products have been shown to accumulate preferentially in senescent endothelial cells,to reduce the expression of cell cycle regulators such as p16,p21 and p53,and to improve the endothelial function.The protective effect is mostly due to their ability to reduce vascular oxidative stress by inhibiting the overexpression of NADPH oxidase and the local angiotensin system.Thus,nutrition-derived polyphenols may be an interesting approach to delay the onset of risk factor-and ageing-related endothelial senescence and dysfunction and,hence,to promote vascular health.
文摘OBJECTIVE To systematically review the clinical efficacy and safety on TCHMs that are used for vascular dementia(VaD).METHODS To identify studies for systematical review,electronic searches were performed through several databases-ALOIS,CNKI,CBM,Weipu,Wanfang,etc.Only randomized control trials(RCTs)or controlled clinical trials(CCTs)were included.Patients were diagnosed with VaD by diagnostic criteria(DSM,NINDS-AIREN,ICD or HIS)as well as imaging technique(CT,MRI or functional imaging,etc).Eligible TCHMs must be recognized in the Chinese Pharmacopeia or the National Essential Drug List of the People′s Republic of China.Included studies were appraised using the Cochrane Collaboration risk-of-bias criteria.Efficacy and safety outcomes were evaluated by meta-analysis.Efficacy outcomes include cognition,daily function,global performance and behaviour;safety was assessed by the number of adverse events and number of subjects experiencing adverse events.Assessment of heterogeneity,subgroup analysis and sensitivity analysis were also performed.RESULTS A total of 46 trials on 29TCHMs(3522patients)were included.45 studies were RCTs and 1was CCT.In these 45 RCTs,only 2were appraised as adequately randomised.5of 46 trials were appraised as having low risk of bias in blinding.Sample sizes were generally small ranging from 26 to 216with a median of 68.All trials were conducted in China from 1997 to 2013.All 46 studies assessed cognition using one or a combination of the following scales:MMSE(n=40 studies;3096 patients),HDS(n=22;1664 patients),ADAS-Cog(n=4;241 patients),CDT(n=1;60patients)and CCSE(n=1;26patients).Half of the studies assessed daily function using either the ADL(n=22;1743 patients)or IADL(n=2;203patients).Only 6studies measured behaviour using the FAQ(n=3;226 subjects),BBS(n=1;48patients),NPI(n=1;100subjects)or Neurological Deficits Function Scale(n=1;91patients).30 studies measured global performance.31 of 46 studies made conclusions regarding the safety of the TCHMs.Despite the problems of methodology and reporting,we can identify three TCHMs-NaoXinTong,Shenfu and Tongxinluo as having relatively stronger evidence of efficacy.There is weak evidence for the safety of TCHMs for VaD.CONCLUSION There is weak evidence for the efficacy and safety of TCHMs for VaD because of the poor methodology,short duration of follow-up and inadequate reporting.However the agents appear to be relatively free of severe short-term AEs,hence we encourage further better designed and reported trials.
基金Natural Science Foundation of China(81573645,81603101)the National Science and Technology Major Project(2013ZX09103001-008)
文摘OBJECTIVE The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling,which is characteristic of pulmonary arterial hypertension(PAH).In this study we exam-ined whether salvianolic acid A(SAA)extracted from the traditional Chinese medicine′Dan Shen′attenuated vascular remodeling in a PAH rat model,and elucidated the underlying mechanisms.METHODS PAH was induced in rats by injecting a single dose of monocrotaline(MCT 60 mg·kg-1,sc).The rats were orally treated with either SAA(0.3,1,3 mg·kg-1·d-1)or a positive control bosentan(30 mg·kg-1·d-1)for 4 weeks.Echocardiography and hemodynamic measurements were performed on d 28.Then the hearts and lungs were harvested,the organ indices and pulmonary artery wall thickness were calculated,and biochemical and histochemical analysis were conducted.The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting.RESULTS Treatment with SAA or bosentan effectively ameliorated MCTinduced pulmonary artery remodeling,pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure(RVSP).Furthermore,the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium,parenchymal injury and collagen deposition in the lungs.Moreover,the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs.The treatments partially restored MCT-induced reductions of bone morphogenetic protein typeⅡreceptor(BMPRⅡ)and phosphorylated Smad1/5 in the lungs.CONCLUSION SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRⅡ-Smad pathway and inhibiting apoptosis.Thus,SAA may have therapeutic potential for the patients at high risk of PAH.
文摘OBJECTIVE To investigate the role of adventitial vasa vasorum in artery remodeling during the process of pulmonary artery hypertension(PAH),we checked the small heat shock protein 27/25(HSPB1)whether involved in pathological basis of vascular remodeling.METHODS We explored the potential role of HSPB1 interacts with ectopic F1Fo-ATPase in the pulmonary vascular remodeling,investigate its effects on the endothelium cell dynamic,and further reveal its possible molecular mechanisms using hypoxic pulmonary hypertension rat model,transgenic mice and pulmonary adventitial vasa vasorum endothelial cell culture in vitro.RESULTS Our studies have shown that HSPB1 improves adventitial vasa vasorum angiogenesis and remodeling.We found that hypoxia induces-HSPB1 upregulation and HSPB1 interact with ectopic F1Fo-ATPase modulate adventitial vasa vasorum endothelial cell proliferation,migration and tube formation.And the inhibition of HSPB1can reverse the vascular inflammation and fibrosis amazingly.CONCLUSION Adventitial vasa vasorum plays an important role in vascular remodeling,and small heat shock protein 27/25 was involved in a variety of diseases during the development of PAH,which could an efficient therapeutic targets and prevention strategy for PAH clinical.
基金The project supported by National Natural Science Foundation of China(81102445 and81670456)Beijing Natural Science Foundation(7162132)the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(33320140069)
文摘Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic diseases.Smooth muscle cell(SMC)phenotype change,which has been described as converting from a contractile state into a synthetic phenotype,is a crucial event during vascular remodeling.Recently,micro RNAs(mi RNAs)a kind of small non-coding RNA molecules,has been proven to target critical genes of cell signaling pathways to regulate SMC phenotypic change.By searching the Pub Med,Embase,reviews,and reference listsof relevant papers,we systematically carried out a review of the literature to provide an overview of the mi RNAs and their target genes in cell signaling pathways,focus inthe pathways involving in SMC phenotype change.To be specific,mi RNAs that regulate genes involved in the MAPK signaling pathways(such as:mi R-155,mi R-92a,mi R-424/503,mi R-133,mi R-181b,mi R-31,mi R-1298,mi R-132,mi R-200c and mi R-483-3p),mi RNAs target genes involved in the TGF-βsignaling pathways(including mi R-24,mi R-17/92 cluster,mi R-599,mi R-21 and mi R-143/145),mi RNAs target the genes involved in the AMPK signaling pathways including mi R-144/451 and mi R-195,mi RNAs target the genes involved in the PI3K-Akt signaling pathways(including mi R-138,mi R-34c,mi R-223,mi R-761,mi R-10a,mi R-146a),mi R-199a-5ptargets the genes involved in the Wnt signaling pathways mi RNAs(mi R-221/222,mi R-15b,mi R-24/29a,mi R-224)involved in the PDGF signaling pathways and some mi RNAs(mi R-638,mi R-328,mi R-365,mi R-663,mi R-29b,mi R-130,mi R-142-5p,mi R-424/322)which regulate SMC phenotype change by other corresponding targets were in detailed discussed in our review.Exploring the regulation of miR NAs in key cellsignaling pathways-mediatedvascular remodeling wil have momentous impact on identifying novel therapeutic targets for its associated disease.
基金The project supported by National Natural Science Foundation of China(81273512,81460010)by Natural Science Foundation of Jiangxi province(20142BAB215035)
文摘OBJECTIVE To explore the role of calpain in in pulmonary vascular remodeling in hypoxia induced pulmonary hypertension and the underlying mechanism.METHODS Sprague-Dawley rats were randomly divided into hypoxia group and normoxia control group.Right ventricular systolic pressure(RVSP)and mean pulmonary artery pressure(m PAP)were monitored by the method of right external jugular vein cannula.Right ventricular hypertrophy index was expressed as the ratio of right ventricular weight to left ventricular weight(left ventricle plus septum weight).Level of calpain-1,calpain-2and calpain-4 m RNA in pulmonary artery trunk were determined by real-time PCR.Expression of calpain-1,calpain-2 and calpain-4 protein was determined by Western Blot.Primary rat pulmonary arterial smooth muscle cells(PASMCs)were divided into 4 groups:normoxia control group,normoxia+MDL28170 group,hypoxia group and hypoxia+MDL28170 group.Cell proliferation was detected by MTS and flow cytometry.Level of Ki-67 and PCNA m RNA were determined by real-time PCR.RESULTS RVSP,m PAP and right ventricular remodeling index were significantly higher in the hypoxia group than those in the normoxia group.In the hypoxia group,pulmonary vascular remodeling occurred,and the expression of calpain-1,calpain-2 and calpain-4 m RNA and protein expression was increased in the pulmonary artery.MDL28170 significantly inhibited hypoxia-induced proliferation of PASMCs accompanied with decreased Ki-67and PCNA m RNA expression.CONCLUSION Calpain mediated vascular remodeling via promoting proliferation of PASMCs in hypoxia induced pulmonary hypertension.
基金supported by grants from the National Natural Science Foundation of China ( 11625209,11572199,31670958)
文摘Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodeling is abnormal variations of vascular cell phenotype,morphological structure and functions such as migration,hypertrophy,proliferation and apoptosis.Numerous researches revealed that mechanical stress,including shear stress and cyclic stretch,participates in physiological vascular homeostasis,or pathophysiological vascular remodeling.The understanding of mechanobiological mechanism in vascular remodeling will play a unique role in understanding human physiology and disease,and will generate important theoretical and clinical significance [2].Non-coding RNAs are newly recognized RNAs which cannot be translated into proteins but are involved in epigenetic modification of gene regulation.The studies revealed that non-coding RNAs,such as microRNAs(miRNAs)and long noncoding RNAs(long ncRNAs,IncRNA),as well as small interfering RNAs(siRNAs),piwi-interacting RNAs(piRNAs),small nucleolar RNAs(snoRNAs),play essential roles in the regulation of various processes,such as metabolism,development,cell proliferation,cell apoptosis,cell differentiation,oncogenesis and vascular homeostasis[5].However,the roles of non-coding RNAs in the cardiovascular system under mechanical stresses are still not clarified.Our recent researches detected the mechanical regulation of IncRNAs and miRNAs in vascular remodeling.LncRNAs are non-protein-coding transcripts that are longer than 200 nucleotides(nt),which is an arbitrary cut-off value that distinguishes these transcripts from other small RNAs.Unlike the well-established mechanism of microRNA action,the functional mode of IncRNAs is not fully understood.Increasing evidence shows that IncRNAs modulate gene expression via a multilevel-regulated pathway.Given their large number and complicated functional modes,lncRNAs are emerging as important regulators of a variety of cellular responses,developmental processes and diseases.Using a gene microarray,we screened the differences in the IncRNAs and mRNAs between spontaneously hypertensive rats(SHR)and Wistar Kyoto rats(WKY).The results showed that 68 IncRNAs and 255 mRNAs were up-regulated in the aorta of SHR,while 167 IncRNAs and 272 mRNAs were down-regulated.Expressions of the screened IncRNAs,including XR007793,were validated by real-time PCR.A co-expression network was composed,and gene function was analysed using Ingenuity Pathway Analysis.In vitro,vascular smooth muscle cells(VSMCs)were subjected to cyclic stretch at a magnitude of 5%(physiological normotensive cyclic stretch)or 15%(pathological hypertensive cyclic stretch)by Flexercell-5000TM.15%-cyclic-stretch increased XR007793 expression.XR007793 knockdown attenuated VSMC proliferation and migration and inhibited co-expressed genes such as signal transducers and activators of transcription 2(stat2),LIM domain only 2(lmo2)and interferon regulatory factor 7(irf7)[4].Illuminating the role of IncRNAs in vascular remodeling induced by hyper mechanical stretch may provide deeper insight into the mechanobiological mechanism underlying hypertension,and contribute to identifying potential targets for hypertension therapy.miRNAs are endogenous,non-coding,single-stranded RNAs of 18-22 nucleotides that constitute a novel class of gene regulators.miRNAs bind to their target genes within their 3’-untranslated regions(3’-UTRs),leading to direct degradation of mRNA or translational repression by a complete,i.e.in plants,or incomplete,i.e.in animals,complement respectively.Our resent works revealed several important mechano-responsive miRNA and their potential effects in vascular remodeling.Forexample,miRNA-33 is regulated by cyclic stretch in the grafted vessels,which targets to BMP3 and subsequent modulates smad signaling pathway.The miRNA-33-BMP3-smad pathway protects against venous VSMC proliferation in response to arterial cyclic stretch.Therefore,miRNA-33 may be a potential therapeutic target in autologous vein grafted surgery,and locally overexpression of miR-33 may attenuates neointimal hyperplasia of grafted human saphenous vein [3].The unpublished data revealed that 15%cyclic stretch also significantly elevated the expression of miRNA-124-3p which bound to the 3’UTR of Lmna mRNA,and then negatively regulated protein expression of lamin A/C which is the important skeletal proteins in nucleus.In addition to primary intracellular locations of miRNAs,our recent study showed that miRNAs can be secreted and protected extracellularly via inclusion into membrane-derived vesicles including microparticles.Microparticles are extracellular vesicles ranging from 0.1 to 1μm in size and have been shown to deliver various bioactive molecules,i.e.,chemokines,enzymes and miRNAs,to recipient cells.Increasing evidence shows that microparticles play a pivotal role in many pathological processes,such as cancer,inflammatory diseases and cardiovascular disease.Our present study showed that platelet-derived microparticles(PMPs),which are released by active platelets,are important vehicles for communication and play crucial roles in inducing abnormal EC proliferation in hypertension.In briefly,EC proliferation was increased in renal hypertensive rats established by abdominal aortic coarctation compared to control rats and that elevated thrombin in plasma promoted platelet activation,which may induce the release of PMPs.miRNA array and qPCR revealed a higher level of miRNA-142-3p in platelets and PMPs.In vitro,PMPs delivered miRNA-142-3p into ECs and enhanced EC proliferation via Bcl-2-associated transcription factor 1(BCLAF1)and its downstream genes.These results indicated that PMPs deliver miRNA-142-3p from activated platelets into ECs and that miRNA-142-3p may play important roles in EC dysfunction under hypertensive conditions and might be a novel therapeutic target for maintaining EC homeostasis in hypertension[1].These results provide possible mechanisms by which non-coding RNAs regulate cellular functions under different mechanical stresses,and suggest a novel potential therapeutic approach for vascular remodeling.The further studies on noncoding RNAs may provide new insight into understanding the mechanism of vascular remodeling in different various cardiovascular disorders,and may provide novel targets for the maintenance of vascular homeostasis.
文摘Pathological vascular remodeling is characterized by thickening or thinning of the vessel wall through altering cellular and non-cellular components,which associates with various blood circulation disorders in brain,heart,lung,and peripheral vasculatures. Pathological vascular remodeling occurs in response to a variety of vascular insults such as mechanical(angioplasty or stenting) or biological(lipids,diabetes,smoking,or virus) injuries. It is a polygenic process involving multiple cell types in the vessel wall or circulation,including endothelial cells(ECs),smooth muscle cells(SMCs),fibroblasts,leukocytes,and platelets. One of hallmarks is the transition of vascular smooth muscle cells(SMCs)from a differentiated/quiescent contractile phenotype to a myofibroblast-like dedifferentiated/active so-called synthetic phenotype. Synthetic SMCs are proliferatory,migratory,secretory and inflammatory,playing key roles in the pathogenesis of vascular remodeling. In the normal vessel,ECs synthesize and secrete biological substances such as prostacyclins(PGI_2) and nitric oxide(NO) that not only function as vasodilators but also inhibit SMC phenotype transition and other properties associated with the synthetic phenotype. Cyclic nucleotides cAMP and cGMP are primary mediators of PGI_2 and NO,respectively,and play critical roles in control vascular structural integrity and function. Cyclic nucleotides are controlled by selective activation or inhibition of distinct cyclic nucleotide phosphodiesterase(PDE) isozymes catalyzing the degradation reaction. To date,more than 60 different PDE isoenzymes derived from 22 genes are identified and grouped into 11 broad families(PDE1-PDE11). PDEs are expressed in a cell/tissue-specific manner and only a few enzymes are expressed in any single cell type. Through systematic assessment of the expression levels of all known PDE isoforms in contractile versus synthetic SMCs,we found that the expression levels of a number of PDE are significantly altered between two SMC phenotypes. We then explored the functional roles and underlying mechanisms of these altered PDEs in vascular SMCs pathogenesis and vascular remodeling in vitro and in vivo using a variety of gain-of-or loss-of-function approaches. For example,we found that Ca^(2+)/calmodulinstimulated cAMP/cGMP-hydrolyzing PDE 1C is selectively expressed in synthetic SMCs in vitro and in various vascular disease models in vivo. PDE 1C upregulation contributes to a number of pathogenic functions of synthetic SMCs,such as cell proliferation,migration,and matrix protein metabolism.PDE 1C deficiency markedly attenuates intimal hyperplasia,atherosclerosis,and aortic aneurysm in experimental mouse disease models. These findings suggest that PDE 1C functions as a key regulator of the synthetic SMC pathology in vascular remodeling. Inhibiting PDE 1C function may represent a novel therapeutic strategy for protecting against the pathogenesis of vascular diseases.
文摘Mechanobiology is the study of how stress and strain are generated by cells and how these mechanical factors regulate cell morphology and function.The vascular system is subject to tensile and compressive stress and strain in the blood vessel wal that are generated by blood pressure and play a pivotal role in regulating vascular cell activities including proliferation,differentiation,apoptosis,and migration.These cellular processes are essential to vascular development,performance,and pathogenic alterations.Dr.Y.C.Fung has made significant contributions to vascular mechanobiology—establishing the uniform stress theory,addressing the generation and significance of uniform stress and strain across the blood vessel wall,and proposing the stress-growth theory,addressing the role of mechanical stress in regulating cell proliferative ac-tivities(Fung 1984,Fung 1990).These theories have exerted a profound impact on the development of Biomechanics and Mechanobiology in the vascular as well as other systems.
基金supported by grants from the National Natural Science Foundation of China( 11572199 and 11625209)
文摘Objective The apoptosis of vascular smooth muscle cells(VSMCs)influenced by abnormal cyclic stretch is crucial for vascular remodeling during hypertension.We explored that the causes of mechano-responsive lamin A/C changingin aonormai cyclic stretcn and its roles in VSMC apoptosis.Methods and results Our previous vascular proteomics study revealed that LaminA/C is mechano-sensitive molecule.When VSMCs are subjected to cyclic stretch,the expression of LaminA/C is significantly changed which participates dysfunctions of VSMCs during hypertension.However,the molecular mechanism involved in regulation of LaminA/C expression and the role of LaminA/C in the VSMC apoptosis during cyclic stretch application are still unclear.In the present study,VSMCs were subjected to different amplitudes of cyclic steetch in vitro:5%cyclic stretch(physiological strain)or 15%cyclic stretch(pathological strain).The expression of 2 different selective cleavage isomers of LaminA/C,i.e.LaminA and LaminC,and the apoptosis of VSMCs were detected.The results showed that compared with 5%group,15%cyclic stretch significantly decreased the expression of LaminA and LaminC,and promoted the apoptosis of VSMCs.Using specific small interfering RNA(siRNA)transfection which targets on LMNA the encoding gene of LaminA/C,the expression of LaminA and LaminC in VSMCs was significantly decreased,and the apoptosis was significantly increased.In order to study the molecular mechanism involved in cyclic stretch regulating the expression of LaminA/C,we focused on the microRNA(miR).Bioinformatics analysis showed that the 3’untranslated region(3’UTR)of LMNA has two potential binding sites to miR-124-3p.Double luciferase reported system revealed that both sites have binding abilities to miR-124-3p.Under static condition,miR-124-3p inhibitor significantly up-regulated the expression levels of LaminA and LaminC,while the miR-124-3p mimics significantly down-regulated them.RT-PCR results showed that 15%cyclic stretch significantly up-regulated the expression of miR-124-3p compared with 5%cyclic stretch.Furthermore,in order to study the role of changeed LaminA/C in VSMC apoptosis,LMNA-specific siRNA was transfected to repress the expression of LaminA/C in VSMCs,and Protein/DNA microarray was used to detecte the activity of transcription factors.The transcription factors whose activity were changed significantly(increase or decrease more than 2 times)were analyzed by cluster analysis and ingenurity pathway analysis(IPA).Six transcription factors associated with apoptosis were screened,in which TP53 was activated by the specific siRNA transfection and the other 5 were inavtived,including TP53,CREB1,MYC,STAT1/5/6 and JUN.Using abdominal aorta coarctation hypertensive model,the change of miR-124-3p in VSMCs was explored in vivo.A marked increase of miR-124-3p in thoracic aorta was revealed compared with the sham-operated controls,and in situ FISH revealed that this increase was mainly in the VSMCs.Conclusions The present study suggest that abnormally increased cyclic stretch(15%)up-regulates the expression of miR-124-3p in VSMCs,which subsequently targets on the 3’UTR of LMNA and decreases the expression of nuclear envelope protein LaminA/C;the repressed LaminA/C may play an important role in the apoptosis of VSMCs by regulating the activity of virious transcription factors,such as TP53,CREB1,MYC,STAT1/5/6 and JUN.The present study may provide a new insight into understanding the molecular mechanisms of vascular remodeling.
文摘Aim Angiotensin II （AngII） induces vascular smooth muscle cell （VSMC） migration and growth, which is responsible for vascular remodeling during some cardiovascular diseases. It has been demonstrated to activate a C1 current, but the underlying mechanism is not clear. Methods Whole-cell patch clamp, co-immunoprecipitation （co-IP）, site-specific mutagenesis, angiotensinII-infusion hypertensive mice model were used. Results In VSMCs, AngII could induce a C1C-3-dependent C1- current that was abolished in C1C-3 null mice. The activation mechanism of this AngII-induced C1- current was ascribed to the interaction between C1C-3 and Rho-kinase 2 （ROCIL2）, as re- vealed by N-terminal or C-terminal truncation of C1C-3, ROCIC2 siRNA and Co-IP experiments. Then we searched for and identified the phosphorylation site of C1C-3 at threonine 532 is critical for AngII-induced C1- current and VSMC migration through ROCK. The C1C-3 T532D mutant （mutation of threonine 532 to aspartate）, mimicking the phos- phorylation state of C1C-3, significantly potentiated AngII-induced C1- current and VSMC migration; while C1C-3 T532A （mutation of threonine 532 to alanine） had the opposite effects. Furthermore, we found a remarkably de- creased AngII-induced VSMC migration in C1C-3 null mice that is insensitive to Y27632, an inhibitor of ROCIL2. In addition, AngII-induced cerebrovascular remodeling was ameliorated in C1C-3 null mice, possibly by ROCIL2 path- way. Conclusions C1C-3 protein phosphorylation at threonine 532 by ROCIL2 is required for AngII-induced C1- cur- rent and VSMC migration that are involved in AngII-induced hypertensive vascular remodeling.
文摘Aim Alpha7 nicotinic acetylcholine receptor （α7nAChR）, a subtype of nAChR regulating neurotrans- mission in central nervous system, is an essential regulator of cholinergic antiinflammatory pathway in periphery. The present study was to determine the effects of activation of α7nAChR on oxidant stress-induced injury in endo- thelial cells. Methods Cultured human umbilical vein endothelial cells were treated with H202 （400 μmol · L^-1） or H202plus PNU-282987 （ 10 μmol · L^-1 ）. Cell viability and membrane integrity were measured. AnnexinV ＋ PI assay, immunoblotting of bcl-2, bax and cleaved caspase-3, and immunofluorescence of apoptosis inducing factor （AIF） were performed to evaluate apoptosis. Protein expression of vascular peroxidase-1 （ VPO-1 ） and phosphor- JNK were measured by immunoblotting. Results Activation of α7nAChR by a selective agonist PNU-282987 pre-vented H202-indced decrease of cell viability and increase of lactate dehydrogenase release. Activation of α7nAChR markedly reduced cell apoptosis and intracellular oxidative stress level. Moreover, activation of α7nAChR reduced H2 02 -induced VPO-1 protein upregulation and JNK1/2 phosphorylation. The inhibitory effect of α7nAChR activa- tion on VPO-1 was blocked by JNK inhibitor SP600125. In addition, pretreatment of α7nAChR antagonist methyl- lycaconitine blocked the cytoprotective effect of PNU-282987. Conclusion These results provide the first evidence that activation of α7nAChR protects against oxidant stress-induced damage by suppressing VPO-1 in a JNK signa- ling pathway-dependent manner in endothelial cells.
文摘OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with white matter damage,and optogenetics and skin stroking were exerted to activate glutamater⁃gic neurons in the somatosensory cortex in a clas⁃sical mouse model of ischemia vascular dementia.RESULTS White matter damage was correlated with disrupted cortical structure from MRI results.In a mouse model,activating glutamatergic neu⁃rons in the somatosensory cortex promotes prolif⁃eration of OPCs and remyelination to rescue cog⁃nitive impairment after chronic cerebral hypoper⁃fusion.Such therapeutic action was limited to stimulation with moderate intensity at the upper layers of the cortex,but was achieved over a wide time window after ischemia.Mechanistically,enhanced glutamatergic neuron-OPC functional synaptic connections are required for protection from activation of cortical glutamatergic neurons.Finally,skin stroking activation of the somatosen⁃sory cortex,an easier approach for clinical trans⁃lation,promoted OPC proliferation and remyelin⁃ation as well as cognitive recovery after cerebral hypoperfusion.CONCLUSION Activation of gluta⁃matergic neurons in the somatosensory cortex may serve as novel approaches for treating isch⁃emic vascular dementia through precise modula⁃tion of glutamatergic neuron-OPC circuits.
文摘Background and Objective In-stent restenosis(ISR)remains a major limitation of percutaneous coronary intervention despite improvements in stent design and pharmacological agents,whereas the mechanism of ISR has not been fully clarified.In the present study,we sought to investigate the potential association of serum soluble TREM-1(sTREM-1)levels with the incidence of ISR.The role of TREM-1 was evaluated in cultured vascular smooth muscle cells(VSMCs).
基金supported by grants from the National Natural Science Foundation of China,Nos10732070,10702043,30970703,10972140 and 30470432
文摘Instruction Shear stress,caused by the parallel frictional drag force of blood flow,is a biomechanical force which plays an important role in the control of blood vessels growth and functions [1]. Clinical researches had found out that atherosclerotic le-
