Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarge...Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarged cardiomyocyte.Effective intervention targets for abnormally enlarged cardiomyocyte remain to be identified.Previous studies have shown that the cellular shape and size can be regulated by the actin related protein 2/3(Arp2/3)complex,which is an actin-binding protein complex involved in the actin nucleation and assembly.However,the roles of the Arp2/3 complex in cardiomyocyte hypertrophy remain unknown.Here our study identifies its novel roles in the occurrence and development of cardiomyocyte hypertrophy.We found that mRNA levels of all subunits from the Arp2/3 complex are significantly upregulated(P<0.05)in the angiotensin Ⅱ(Ang Ⅱ)-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy.Further studies showed that siRNA-directed ARPC 2 silencing inhibits the reactivation of fetal genes and enlargement of cardiomyocyte area induced by Ang Ⅱ in neonatal rat primary cardiomyocytes(NRCMs)and H9c2 cells(P<0.05).In addition,the upstream activators of the Arp2/3 complex including SH3 protein interacting with Nck,90 kD(SPIN90)and Ras-related C3 botulinum toxin substrate 1(Rac1)/WASp family Verprolin-homologous protein-2(WAVE-2)are upregulated(P<0.05)in Ang Ⅱ-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy,indicating the excessive activation of the Arp2/3 complex.We further show that CK666,a specific Arp2/3 complex inhibitor,prevents the reactivation of fetal genes and the enlargement of cardiomyocyte area induced by Ang Ⅱ in NRCMs and H9c2 cells(P<0.05).Our results reveal that the Arp2/3 complex plays a crucial role in Ang Ⅱ-induced cardiomyocyte hypertrophy,which is beneficial to further studies about the molecular mechanisms by which the Arp2/3 complex regulates pathological cardiac hypertrophy.展开更多
OBJECTIVE Right ventricular(RV)remodeling is one of the essential pathological features in pulmonary arterial hypertension(PAH).RV hypertrophy or fibrosis are the leading causes of RV remodeling.Magnolol is a compound...OBJECTIVE Right ventricular(RV)remodeling is one of the essential pathological features in pulmonary arterial hypertension(PAH).RV hypertrophy or fibrosis are the leading causes of RV remodeling.Magnolol is a compound isolated from Magnolia officinalis.It possesses multiple pharmacological activities,such as anti-oxidation and anti-inflammation.This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH.METHODS①Male SD rats(220 g)were randomly divided into 5 groups(n=10):the normoxia group,the hypoxia group,the hypoxia plus Magnolol(10 and 20 mg·kg^(-1)·d-1)group,and the vehicle group.Rats in the normoxia group were kept in a normoxia environment for 4 weeks,while rats in the hypoxia group were kept in a hypoxic chamber(10%O2).The rats in the hypoxia plus magnolol groups were administered with magnolol at 10 or 20 mg·kg^(-1)(ip)once a day for 4 weeks.At the end of 4 weeks,the heart function was assessed by Doppler echocardiography,and then the rats were anesthetized with sodium pentobarbital(30 mg·kg^(-1),ip).The RVSP was measured by the right heart catheterization method.The heart tissues were collected and dissected to calculate the index of RV remodeling(RV/LV+IVS,RV/tibial length,or RV/body weight).Part of the RV samples was fixed with 4%paraformaldehyde for morphological analysis,while other samples were frozen at-80℃for molecular studies(measurements of ANP,BNP,α-SMA,and collagenⅠ/ⅢmRNA expression as well as p-JAK2/JAK2 and p-STAT3/STAT3 protein levels).②To evaluate the effect of magnolol on hypoxia-induced myocardial hypertrophy and fibrosis,H9c2 or cardiac fibroblasts were divided into 7 groups:the control group,cells were cultured under normal conditions;the hypoxia group,cells were cultured under hypoxic condition(3%O2);the hypoxia plus magnolol 10 mg·kg^(-1) group,magnolol10μmol·L^(-1) was added to the culture medium before the hypoxia treatment;the hypoxia plus magnolol 30 mg·kg^(-1) group,magnolol 20μmol·L^(-1) was added to the culture medium before the hypoxia treatment;the hypoxia plus TG-101348 group,TG-101348(a specific inhibitor of JAK2)1μmol·L^(-1) was added to the culture medium before the hypoxia treatment;the hypoxia plus JSI-124 group,JSI-124(a specific inhibitor of JAK2)1μmol·L^(-1) was added to the culture medium before the hypoxia treatment;and the hypoxia plus vehicle group,an equal volume of vehicle(DMSO)was added to the culture medium before the hypoxia treatment.At the end of the experiments,the cells were collected for morphological and molecular analysis.RESULTS In vivo,male Sprang-Daley rats were exposed to 10%O2 for 4 weeks to establish an RV remodeling model,which showed hypertrophic and fibrotic features(increases of RV remodeling index,cellular size,hypertrophic and fibrotic marker expression),accompanied by an elevation in phosphorylation levels of JAK2 and STAT3;these changes were attenuated by treating rats with magnolol.In vitro,the cultured H9c2 cells or cardiac fibroblasts were exposed to 3%O2 for 48 h to induce hypertrophy or fibrosis,which showed hypertrophic(increases in cellular size as well as the expression of ANP and BNP)or fibrotic features(increases in the expression of collagenⅠ,collagenⅢandα-SMA).Administration of magnolol and TG-101348 or JSI-124 (JAK2 selective inhibitors) could prevent the process of myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. CONCLUSION Magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway.展开更多
Aim As we all know, apelin acts as the endogenous ligand of APJ, being a member of G protein cou- pled receptors family, apelin/APJ system is involved in plentiful diseases and extremely responsible for the occur- ren...Aim As we all know, apelin acts as the endogenous ligand of APJ, being a member of G protein cou- pled receptors family, apelin/APJ system is involved in plentiful diseases and extremely responsible for the occur- rence and the development of cardiovascular diseases, among many kinds of heart diseases, it is the cardiac hyper- trophy that catches our attention. The myocardial expression of apelin/APJ decreased in rats with left ventrieular hypertrophy suggesting us there is a link between apelin and cardiac hypertrophy. Furthermore, it has been repor- ted that apelin is able to alleviate cardiac hypertrophy induced by Ang II, H202 and exercise. Nevertheless, our la- boratory discovered that apelin is certain to induce cardiac hypertrophy through PI3k-Akt-ERK1/2-p70S6K pathway or via up-regulating the levels of ROS to cause oxidative stress. The above-mentioned contradiction indicates us apelin may have dual effects in cardiac hypertrophy. Moreover, we also illuminate that apelin is involved in some diseases such as obesity, diabetes, hypertension, myoearditis and myocardial infarction, eoineidentally, all these diseases are associated with cardiac hypertrophy. Therefore, this review is aim to unveil the intricate relationship between apelin and cardiac hypertrophy.展开更多
Aim The present study aims to investigate whether BMSCs transplantation may inhibit hypertrophic hearts and its underlying mechanisms. Background There is no evidence so far that Bone marrow-derived mesenchy- mal stem...Aim The present study aims to investigate whether BMSCs transplantation may inhibit hypertrophic hearts and its underlying mechanisms. Background There is no evidence so far that Bone marrow-derived mesenchy- mal stem cells （BMSCs） can heal pathological myocardial hypertrophy. Methods To observe the antihypertrophic actions, BMSCs was indirectly cocultured with NRVCs in vitro, or intramyocardially transplanted into hypertrophic hearts in vivo. Results ISO-induced typical hypertrophic characteristics of cardiomyocytes were obviously preven- ted by BMSCs in the co-culture model in vitro and after BMSCs transplantation in vivo. Furthermore, the activation of the Ca2＋/calcineurin/NFATc3 hypertrophic pathway was shown abrogated in the presence of BMSCs both in vitro and in vivo. Interestingly, blockage of VEGF release from BMSCs but not bFGF and IGF-1 can abolish the protec- tive effects of BMSCs on cardiomyocytes hypertrophy. Consistently, VEGF administration attenuated ISO-induced BNP and β-MHC expression and the activation of Ca2＋/cal- the enlargement of cellular size, the augment of ANP, cineurin/NFATc3 hypertrophic pathway, and these can be abrogated by blocking VEGFR-1, indicating VEGFR-1 is involved in the antihypertrophic role of VEGF. We further find that the ample VEGF secretion contributing to the anti-hypertrophic effects of BMSCs originates from BMSCs interplay with cardiac cells but not BMSCs or cardiomyo- cytes alone. Conclusions Thus, mesenchymal stem cells are able to inhibit myocardial hypertrophy via interacting with cardiomyocytes so as to promote VEGF release which inhibits the activation of the Ca2＋/calcineurin/NFATc3 hypertrophic signaling pathway in cardiac cells, in addition to its well-recognized ability to ameliorate myocardial injuries by replacing dead cells.展开更多
Aim Previous studies showed that the inhibition of proteasome activity could significantly improve cardi- ac hypertrophy, but its mechanism is not clear. Increased glycogen synthase kinase-3 （GSK-3） activity can als...Aim Previous studies showed that the inhibition of proteasome activity could significantly improve cardi- ac hypertrophy, but its mechanism is not clear. Increased glycogen synthase kinase-3 （GSK-3） activity can also improve cardiac hypertrophy. However, the relationship between proteasome and GSK-3 has not been reported in cardiomyocyte In this study, we will investigate the effect of proteasome inhibition on cardiomyocyte hypertrophy, GSK-3 activity and the underlying mechanism. Methods Primary neonatal rat cardiomyocytes were divided into 4 groups： Control, Ang H （100 nmol · L^-1 48 h） Ang Ⅱ （ 100 nmol · L^-1） ＋ MG132 （0.05 μmol · L^-1） MG132 （0.05 μmol · L^-1） ,Ang 11 （100 nmol · L^-1 ） ＋ MG132 ＋ LiC1 （ 10 mmol · L^-1 ）, LiC1. Proteasome activitiy was detected by fluorescent peptide substrate. Cardiomyocyte surface area, ANF mRNA expression, and the rate of protein synthesis were observed as myocardial hypertrophy index. GSK-3, Akt, AMPKoL, and Histone3 （H3） were detected by Western Blot. The expression of GATA4 in the cytoplasm and nucleus was observed by im- munofluorescence. Results （1） Compared with the control group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all increased in Ang H group. The chymotrypsin-like, trypsin-like and caspase-like activities of proteasome were all increased significantly. The phosphorylated level of both GSK-3α（ p- GSK-3α） （ Ser21 ） and GSK-3β （p-GSK-3β ） （Ser9） increased, i. e they were inactivated. （2） Compared with the Ang II group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all decreased after proteasome inhibition. And p-GSK-3 （Ser21） and p-GSK-3β （Ser9） was respondingly decreased, （3） Proteasome inhibition also resulted in the decrease of p-Akt （Ser473） and p-AMPKa （Thr172）7 which in- creased in cardiomyocyte hypertrophy. Immunofluorescence showed that GATA4 was mainly distributed in the nu- cleus after Ang II treatment, while it was obviously increased in the cytoplasm after proteasome inhibition. After the GSK-3 inhibitor-LiC1 was given, the above indicators were reversed. （4） p-Histone3 was also increased in cardio- myocyte hypertrophy and MG132 reduced its level, but LiC1 treatment had no significant effect on its level. Con- clusion Proteasome inhibition reduces cardiomyocyte hypertrophy through increase of GSK-3a/b activity, which may be related with the decrease of Akt and AMPKa activities, and the decrease of nucleus location of GATA4, but p-histone3 is not involved.展开更多
Aim To explore the role of transcription factor Foxp3 and the regulating effect of triptolide （TP） in the progression of myocardial hypertrophy in mice. Methods Fifty male mice were randomly divided into 5 groups, i...Aim To explore the role of transcription factor Foxp3 and the regulating effect of triptolide （TP） in the progression of myocardial hypertrophy in mice. Methods Fifty male mice were randomly divided into 5 groups, i. e., normal control group, myocardial hypertrophy model group and TP （10, 30, 90μg · kg^-1） treated groups. Myocardial hypertrophy was induced by isoprenaline （ISO） 5 mg kg^-1 once daily for 14 days. Triptolide was giv- en intraperitoneally once daily. Left ventricle tissue was subjected to HE staining and chemiluminescence technique to assess effects on hypertrophy, fibrosis and inflammation, quantitative assessment of hypertrophy regulatory genes were performed by qPCR and WB. Results After 14 days of treatment, myocardial expressions of Foxp3 and CD4 were significantly reduced in the model group compared with controls. The expression level of TGFβ1 in control group was lower, while that in model group increased obviously. TP could significantly lessen myocardial tissue damage, and reduce the heart index and left ventricular index. Compared with model group, TP （30, 90 μg · kg^-1 ） significantly increased myocardial expression ratio of α-MHC to β-MHC, reduced serumal levels of BNP and troponin I, elevated mRNA and protein expressions of Foxp3 and CD4 in myocardial tissue and reduced the protein expression of TGFβ1 by comparison of those in model group. Conclusion TP can effectively ameliorate myocardial damage and inhibit left ventricular remodeling through elevating the expression of CD4 and Foxp3 and decreasing that of TGF-β.展开更多
OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model ...OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.展开更多
Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta...Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.展开更多
文摘Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarged cardiomyocyte.Effective intervention targets for abnormally enlarged cardiomyocyte remain to be identified.Previous studies have shown that the cellular shape and size can be regulated by the actin related protein 2/3(Arp2/3)complex,which is an actin-binding protein complex involved in the actin nucleation and assembly.However,the roles of the Arp2/3 complex in cardiomyocyte hypertrophy remain unknown.Here our study identifies its novel roles in the occurrence and development of cardiomyocyte hypertrophy.We found that mRNA levels of all subunits from the Arp2/3 complex are significantly upregulated(P<0.05)in the angiotensin Ⅱ(Ang Ⅱ)-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy.Further studies showed that siRNA-directed ARPC 2 silencing inhibits the reactivation of fetal genes and enlargement of cardiomyocyte area induced by Ang Ⅱ in neonatal rat primary cardiomyocytes(NRCMs)and H9c2 cells(P<0.05).In addition,the upstream activators of the Arp2/3 complex including SH3 protein interacting with Nck,90 kD(SPIN90)and Ras-related C3 botulinum toxin substrate 1(Rac1)/WASp family Verprolin-homologous protein-2(WAVE-2)are upregulated(P<0.05)in Ang Ⅱ-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy,indicating the excessive activation of the Arp2/3 complex.We further show that CK666,a specific Arp2/3 complex inhibitor,prevents the reactivation of fetal genes and the enlargement of cardiomyocyte area induced by Ang Ⅱ in NRCMs and H9c2 cells(P<0.05).Our results reveal that the Arp2/3 complex plays a crucial role in Ang Ⅱ-induced cardiomyocyte hypertrophy,which is beneficial to further studies about the molecular mechanisms by which the Arp2/3 complex regulates pathological cardiac hypertrophy.
文摘OBJECTIVE Right ventricular(RV)remodeling is one of the essential pathological features in pulmonary arterial hypertension(PAH).RV hypertrophy or fibrosis are the leading causes of RV remodeling.Magnolol is a compound isolated from Magnolia officinalis.It possesses multiple pharmacological activities,such as anti-oxidation and anti-inflammation.This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH.METHODS①Male SD rats(220 g)were randomly divided into 5 groups(n=10):the normoxia group,the hypoxia group,the hypoxia plus Magnolol(10 and 20 mg·kg^(-1)·d-1)group,and the vehicle group.Rats in the normoxia group were kept in a normoxia environment for 4 weeks,while rats in the hypoxia group were kept in a hypoxic chamber(10%O2).The rats in the hypoxia plus magnolol groups were administered with magnolol at 10 or 20 mg·kg^(-1)(ip)once a day for 4 weeks.At the end of 4 weeks,the heart function was assessed by Doppler echocardiography,and then the rats were anesthetized with sodium pentobarbital(30 mg·kg^(-1),ip).The RVSP was measured by the right heart catheterization method.The heart tissues were collected and dissected to calculate the index of RV remodeling(RV/LV+IVS,RV/tibial length,or RV/body weight).Part of the RV samples was fixed with 4%paraformaldehyde for morphological analysis,while other samples were frozen at-80℃for molecular studies(measurements of ANP,BNP,α-SMA,and collagenⅠ/ⅢmRNA expression as well as p-JAK2/JAK2 and p-STAT3/STAT3 protein levels).②To evaluate the effect of magnolol on hypoxia-induced myocardial hypertrophy and fibrosis,H9c2 or cardiac fibroblasts were divided into 7 groups:the control group,cells were cultured under normal conditions;the hypoxia group,cells were cultured under hypoxic condition(3%O2);the hypoxia plus magnolol 10 mg·kg^(-1) group,magnolol10μmol·L^(-1) was added to the culture medium before the hypoxia treatment;the hypoxia plus magnolol 30 mg·kg^(-1) group,magnolol 20μmol·L^(-1) was added to the culture medium before the hypoxia treatment;the hypoxia plus TG-101348 group,TG-101348(a specific inhibitor of JAK2)1μmol·L^(-1) was added to the culture medium before the hypoxia treatment;the hypoxia plus JSI-124 group,JSI-124(a specific inhibitor of JAK2)1μmol·L^(-1) was added to the culture medium before the hypoxia treatment;and the hypoxia plus vehicle group,an equal volume of vehicle(DMSO)was added to the culture medium before the hypoxia treatment.At the end of the experiments,the cells were collected for morphological and molecular analysis.RESULTS In vivo,male Sprang-Daley rats were exposed to 10%O2 for 4 weeks to establish an RV remodeling model,which showed hypertrophic and fibrotic features(increases of RV remodeling index,cellular size,hypertrophic and fibrotic marker expression),accompanied by an elevation in phosphorylation levels of JAK2 and STAT3;these changes were attenuated by treating rats with magnolol.In vitro,the cultured H9c2 cells or cardiac fibroblasts were exposed to 3%O2 for 48 h to induce hypertrophy or fibrosis,which showed hypertrophic(increases in cellular size as well as the expression of ANP and BNP)or fibrotic features(increases in the expression of collagenⅠ,collagenⅢandα-SMA).Administration of magnolol and TG-101348 or JSI-124 (JAK2 selective inhibitors) could prevent the process of myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. CONCLUSION Magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway.
文摘Aim As we all know, apelin acts as the endogenous ligand of APJ, being a member of G protein cou- pled receptors family, apelin/APJ system is involved in plentiful diseases and extremely responsible for the occur- rence and the development of cardiovascular diseases, among many kinds of heart diseases, it is the cardiac hyper- trophy that catches our attention. The myocardial expression of apelin/APJ decreased in rats with left ventrieular hypertrophy suggesting us there is a link between apelin and cardiac hypertrophy. Furthermore, it has been repor- ted that apelin is able to alleviate cardiac hypertrophy induced by Ang II, H202 and exercise. Nevertheless, our la- boratory discovered that apelin is certain to induce cardiac hypertrophy through PI3k-Akt-ERK1/2-p70S6K pathway or via up-regulating the levels of ROS to cause oxidative stress. The above-mentioned contradiction indicates us apelin may have dual effects in cardiac hypertrophy. Moreover, we also illuminate that apelin is involved in some diseases such as obesity, diabetes, hypertension, myoearditis and myocardial infarction, eoineidentally, all these diseases are associated with cardiac hypertrophy. Therefore, this review is aim to unveil the intricate relationship between apelin and cardiac hypertrophy.
文摘Aim The present study aims to investigate whether BMSCs transplantation may inhibit hypertrophic hearts and its underlying mechanisms. Background There is no evidence so far that Bone marrow-derived mesenchy- mal stem cells （BMSCs） can heal pathological myocardial hypertrophy. Methods To observe the antihypertrophic actions, BMSCs was indirectly cocultured with NRVCs in vitro, or intramyocardially transplanted into hypertrophic hearts in vivo. Results ISO-induced typical hypertrophic characteristics of cardiomyocytes were obviously preven- ted by BMSCs in the co-culture model in vitro and after BMSCs transplantation in vivo. Furthermore, the activation of the Ca2＋/calcineurin/NFATc3 hypertrophic pathway was shown abrogated in the presence of BMSCs both in vitro and in vivo. Interestingly, blockage of VEGF release from BMSCs but not bFGF and IGF-1 can abolish the protec- tive effects of BMSCs on cardiomyocytes hypertrophy. Consistently, VEGF administration attenuated ISO-induced BNP and β-MHC expression and the activation of Ca2＋/cal- the enlargement of cellular size, the augment of ANP, cineurin/NFATc3 hypertrophic pathway, and these can be abrogated by blocking VEGFR-1, indicating VEGFR-1 is involved in the antihypertrophic role of VEGF. We further find that the ample VEGF secretion contributing to the anti-hypertrophic effects of BMSCs originates from BMSCs interplay with cardiac cells but not BMSCs or cardiomyo- cytes alone. Conclusions Thus, mesenchymal stem cells are able to inhibit myocardial hypertrophy via interacting with cardiomyocytes so as to promote VEGF release which inhibits the activation of the Ca2＋/calcineurin/NFATc3 hypertrophic signaling pathway in cardiac cells, in addition to its well-recognized ability to ameliorate myocardial injuries by replacing dead cells.
文摘Aim Previous studies showed that the inhibition of proteasome activity could significantly improve cardi- ac hypertrophy, but its mechanism is not clear. Increased glycogen synthase kinase-3 （GSK-3） activity can also improve cardiac hypertrophy. However, the relationship between proteasome and GSK-3 has not been reported in cardiomyocyte In this study, we will investigate the effect of proteasome inhibition on cardiomyocyte hypertrophy, GSK-3 activity and the underlying mechanism. Methods Primary neonatal rat cardiomyocytes were divided into 4 groups： Control, Ang H （100 nmol · L^-1 48 h） Ang Ⅱ （ 100 nmol · L^-1） ＋ MG132 （0.05 μmol · L^-1） MG132 （0.05 μmol · L^-1） ,Ang 11 （100 nmol · L^-1 ） ＋ MG132 ＋ LiC1 （ 10 mmol · L^-1 ）, LiC1. Proteasome activitiy was detected by fluorescent peptide substrate. Cardiomyocyte surface area, ANF mRNA expression, and the rate of protein synthesis were observed as myocardial hypertrophy index. GSK-3, Akt, AMPKoL, and Histone3 （H3） were detected by Western Blot. The expression of GATA4 in the cytoplasm and nucleus was observed by im- munofluorescence. Results （1） Compared with the control group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all increased in Ang H group. The chymotrypsin-like, trypsin-like and caspase-like activities of proteasome were all increased significantly. The phosphorylated level of both GSK-3α（ p- GSK-3α） （ Ser21 ） and GSK-3β （p-GSK-3β ） （Ser9） increased, i. e they were inactivated. （2） Compared with the Ang II group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all decreased after proteasome inhibition. And p-GSK-3 （Ser21） and p-GSK-3β （Ser9） was respondingly decreased, （3） Proteasome inhibition also resulted in the decrease of p-Akt （Ser473） and p-AMPKa （Thr172）7 which in- creased in cardiomyocyte hypertrophy. Immunofluorescence showed that GATA4 was mainly distributed in the nu- cleus after Ang II treatment, while it was obviously increased in the cytoplasm after proteasome inhibition. After the GSK-3 inhibitor-LiC1 was given, the above indicators were reversed. （4） p-Histone3 was also increased in cardio- myocyte hypertrophy and MG132 reduced its level, but LiC1 treatment had no significant effect on its level. Con- clusion Proteasome inhibition reduces cardiomyocyte hypertrophy through increase of GSK-3a/b activity, which may be related with the decrease of Akt and AMPKa activities, and the decrease of nucleus location of GATA4, but p-histone3 is not involved.
文摘Aim To explore the role of transcription factor Foxp3 and the regulating effect of triptolide （TP） in the progression of myocardial hypertrophy in mice. Methods Fifty male mice were randomly divided into 5 groups, i. e., normal control group, myocardial hypertrophy model group and TP （10, 30, 90μg · kg^-1） treated groups. Myocardial hypertrophy was induced by isoprenaline （ISO） 5 mg kg^-1 once daily for 14 days. Triptolide was giv- en intraperitoneally once daily. Left ventricle tissue was subjected to HE staining and chemiluminescence technique to assess effects on hypertrophy, fibrosis and inflammation, quantitative assessment of hypertrophy regulatory genes were performed by qPCR and WB. Results After 14 days of treatment, myocardial expressions of Foxp3 and CD4 were significantly reduced in the model group compared with controls. The expression level of TGFβ1 in control group was lower, while that in model group increased obviously. TP could significantly lessen myocardial tissue damage, and reduce the heart index and left ventricular index. Compared with model group, TP （30, 90 μg · kg^-1 ） significantly increased myocardial expression ratio of α-MHC to β-MHC, reduced serumal levels of BNP and troponin I, elevated mRNA and protein expressions of Foxp3 and CD4 in myocardial tissue and reduced the protein expression of TGFβ1 by comparison of those in model group. Conclusion TP can effectively ameliorate myocardial damage and inhibit left ventricular remodeling through elevating the expression of CD4 and Foxp3 and decreasing that of TGF-β.
基金National Natural Science Foundation of China(81860732)Scientific and Technological Projects for Social Development in Guizhou Province of China([2011]3036)the State Key Laboratory of Cardiovascular Disease(2017kf-03)
文摘OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.
文摘Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.
