Aim Salvia miltiorrhiza Bunge （SM） and lignum dalbergiae odoriferae （DO） are both traditional Chi- nese medicine that have cardioprotective effects. Here, we further examined the combined effects of SM and DO on r...Aim Salvia miltiorrhiza Bunge （SM） and lignum dalbergiae odoriferae （DO） are both traditional Chi- nese medicine that have cardioprotective effects. Here, we further examined the combined effects of SM and DO on rat myocardial ischemia/reperfusion injury. The possible mechanism of SM and DO also were elucidated. Methods DO was divided into aqueous extract of lignum dalbergiae odoriferae （DOW） and lignum dalbergiae odoriferae oil （DOO）. Sprague-Dawley rats were randomized to seven groups： sham group, model group, treatment groups inclu- ding SM （10 g · kg^-1）, DOW （5 g · kg^-1）, DOO （0.5 ml · kg^-1）, SM ＋ DOW （10 g · kg^-1 ＋ 5 g · kg^-1）, SM ＋ DOO （ 10 g · kg^-1 ＋ 0. 5 ml · kg^-1）. Rats were pretreated with homologous drug for 7 days and then subjec- ted to 30 rain of ischemia followed by 180 rain of reperfusion. Electrocardiogram （ECG） and heart rate were moni- tored and recorded continuously. At the end of reperfusion, blood samples were collected to determine the serum levels of creatine kinase-MB （CK-MB） and lactate dehydrogenase （LDH）. Hearts were harvested to assess heart- body rate, infarct size and histopathological changes as well. Maximum and minimum effective points were deter- mined by measuring indicators associate with myocardial injury at different time-points of reperfusion （Smin, 15min, 30min, 45rain, 60min, 120min, 180min）. The potential therapeutic mechanism of SM and SM ＋ DOO were carried out by detecting superoxide dismutase （SOD）, malondialdehyde （MDA）, tumor necrosis factor-alpha （TNF-alpha） and interleukin 6 （IL-6）. Results The results showed SM and DO can ameliorate cardiac function respectively, and this cardioprotective effect was further strengthened by their combinations. Among all the combi- nations, SM ＋ DOO showed predominant potential to improve ECG and heart rate, reduce heart-body rate （28.5% ＋ 1.4% , P 〈 0.01 vs model） and myocardial infarct size （ 20.96% ＋ 1.61% , P 〈 0.01 vs model, P 〈 0.05 vs SM） , attenuate histopathological damage, decrease the levels of CK-MB and LDH （P 〈 0.01 vs model, P 〈 0.05 vs SM）. The maximum effective points of SM and SM ＋ DOO were 15min and 30rain respectively, and the minimum effective points of them were 180rain. In reducing serum level of MDA, TNF-alpha, IL-6 and increasing SOD activ- ity, SM ＋ DOO was similar to SM. Conclusion The results of this study indicated that SM ＋ DOO have combined effects that are highly effective than single pretreatment against myocardial ischemie reperfusion injury in rats. The possible mechanism of SM and DO were likely through its anti-oxidant and anti-inflammatory properties, and thus may be an effective and promising medicine for both prophylaxis and treatment of ischemic heart disease.展开更多
OBJECTIVE In this study we explored the role of Epac1-Rap1 pathway in the acute myocardial ischemia/reperfusion injury(MIRI) in vitro and in vivo.METHODS An acute myocardial ischemia/reperfusion injury model was estab...OBJECTIVE In this study we explored the role of Epac1-Rap1 pathway in the acute myocardial ischemia/reperfusion injury(MIRI) in vitro and in vivo.METHODS An acute myocardial ischemia/reperfusion injury model was established by the ligation of left anterior descending coronary.Myocardial architecture,fibers and apoptosis was evaluated by the Masson trichrome staining,Sirius red staining and TUNEL assay.H9c2 cells were subjected to hypoxia for 5 h followed by 1-h reoxygen.ation in vitro.Cell viability was measured by MTT assay and cellular injury was evaluated by measuring the release of lactate dehydrogenase(LDH).Western blot,real-time PCR and immunofluorescence were used to detect the expressions of Epac1 and relative downstream molecules.RESULTS Myocardial IR-induced cardiac apoptosis and accumulation of Epac1 and Rap1 in rat IR injury model.Direct Epac activation by 8-CPT(8-(4-chlorophenylthio)-2′-O-methyl-cAMP) exacerbated cardiomyocyte death and dysfunction following hypoxia-reoxygenation(H/R),selective activation of Epac in response to H/R was evident which enriched for cytosolic/membrane proteins and mRNA.Harmacological inhibitor of Epac(ESI-09) significantly ameliorated myocardial injury with the decline of Epac expression.Epac inhibitor and agonist studies also implicated the effect of Rap1,which is downstream of Epac in this pathway.The expression of Rap1 elevated when activated by Epac agonist and was blocked by Epac inhibitor.The same result was true for myocyte CaMK-II and intracellular calcium ions activation.Moreover,ESI-09 also increased ERK1/2 phosphorylation.CONCLUSION Our study reveal that Epac1/Rap1 signaling pathway is involved in the pathogenesis of myocardial I/R injury in rats,which provides evidence on the development of therapeutic strategies target this pathway for myocardial I/R injury.展开更多
The morbidity and mortality of cardiovascular diseases are very high,which has attracted more and more attention all over the world.Common treatment methods for clinical treatment of acute myocardial infarction includ...The morbidity and mortality of cardiovascular diseases are very high,which has attracted more and more attention all over the world.Common treatment methods for clinical treatment of acute myocardial infarction include direct percutaneous coronary intervention and coronary artery bypass grafting,which can quickly restore blocked coronary blood flow and reduce the infarct size.However,the inevitable ischemia/reperfusion injury will occur during the recovery of coronary blood flow,its pathological mechanism is complicated,and the Western medicine countermeasures are very limited.Among the current drugs for the treatment of cardiovascular diseases,traditional Chinese medicine has become a research hotspot due to its multiple targets,safety,and low side effects.Ginger is the fresh rhizome of Zingiber officinale Rosc.,a perennial herbaceous plant in the ginger family.It is a dual-purpose resource of medicine and food.Ginger has the functions of relieving the appearance and dispelling cold,warming up and relieving vomiting,resolving phlegm and relieving cough,and relieving fish and crab poison.The chemical components of ginger mainly include volatile oil,gingerol,diphenylheptane,etc..Among them,6-gingerol,as the main active component of gingerols,has obvious pharmacological effects in myocardial protection,anti-oxidation,anti-inflammatory,etc..Studies have shown that 6-gingerol protects myocardium mainly through anti-oxidative stress,anti-inflammatory,inhibiting cell apoptosis,and preventing calcium influx.①Anti-oxidative stress:oxidative stress is a state where oxidation and anti-oxidation in the body are out of balance,and it is also an important factor leading to myocardial damage.Many studies have confirmed that 6-gingerol has an antioxidant effect,and it is considered a natural antioxidant.6-gingerol can significantly reduce the degree of oxidative stress and the level of reactive oxygen species caused by cardiomyocyte damage,and has a significant cardioprotective effect.②Anti-inflammatory:inflammation can cause substantial cell damage and organ dysfunction,which is another important cause of myocardial damage.6-gingerol can reduce the levels of inflammatory factors such as interleukin-6,interleukin-1β,and tumor necrosis factor-αin cardiomyocytes,and at the same time inhibit the TLR4/NF-κB signaling pathway,an important regulatory pathway of inflammation,showing that it may improve myocardial damage through anti-inflammatory effects.③Inhibition of apoptosis:apoptosis is a complex and orderly process in the autonomous biochemical process of cells,and one of the main mechanisms of myocardial injury.This process can be roughly divided into three pathways:mitochondria,endoplasmic reticulum,and death receptors.Among them,the mitochondrial pathway plays an important role,and Bcl-2 and Bax located upstream of this pathway can regulate the entire process of cell apoptosis by regulating the permeability of the mitochondrial membrane.Studies have found that the preventive application of 6-gingerol can reduce cell damage,reduce the number of apoptotic cells,reduce the activity of Bax and caspase-3,and increase the expression of Bcl-2.Therefore,6-gingerol pretreatment can reduce the damage of cardiomyocytes,and its mechanism may be related to the inhibition of apoptosis.④Prevent calcium influx:calcium overload is involved in the pathogenesis of myocardial ischemic injury,which may be related to excessive contracture,arrhythmia,and mitochondrial Ca2+accumulation that impairs myocardial function.6-gingerol inhibits the increase of intracellular Ca2+concentration by inhibiting L-type calcium current,thereby reducing extracellular Ca2+influx,thereby avoiding calcium overload and playing a cardioprotective effect.In summary,6-gingerol can effectively treat and improve myocardial ischemia/reperfusion injury,and it has great development potential in the fields of medicine and health products.展开更多
Myocardial infarction resulting from coronary atherosclerosis is the leading cause of death in modern soci- ety. Reperfusion is an essential treatment to salvage ischemia myocardium from necrosis, while it also leads ...Myocardial infarction resulting from coronary atherosclerosis is the leading cause of death in modern soci- ety. Reperfusion is an essential treatment to salvage ischemia myocardium from necrosis, while it also leads to addi- tional damage. Therefore, exploring effective medicines to protect the heart from post-ischemic injury is one of the major objectives of cardiovascular research. Berbamine is a nature compound of bisbenzylisochinoline alkaloids from Barberry. We found that it displays positive inotropic and lusitropic effects at lower concentrations by increasing myofilament Ca2＋ sensitivity via a PKCe-dependent signaling pathway. Moreover, berbamine preconditioning con- fers cardioprotection against ischemia/reperfusion （I/R） injury by attenuating the Ca2＋ overloading and preventing the calpain activation through the activating of PI3K-Akt-GSK3β pathway and subsequently opening of the mitoKATP channel. Furthermore, we demonstrate that berbamine postconditioning conferred the cardioprotective effect against I/R injury by the regulation of autophagy. These findings reveal new roles and mechanisms of berbamine in the heart and cardioprotection against I/R injury.展开更多
文摘Aim Salvia miltiorrhiza Bunge （SM） and lignum dalbergiae odoriferae （DO） are both traditional Chi- nese medicine that have cardioprotective effects. Here, we further examined the combined effects of SM and DO on rat myocardial ischemia/reperfusion injury. The possible mechanism of SM and DO also were elucidated. Methods DO was divided into aqueous extract of lignum dalbergiae odoriferae （DOW） and lignum dalbergiae odoriferae oil （DOO）. Sprague-Dawley rats were randomized to seven groups： sham group, model group, treatment groups inclu- ding SM （10 g · kg^-1）, DOW （5 g · kg^-1）, DOO （0.5 ml · kg^-1）, SM ＋ DOW （10 g · kg^-1 ＋ 5 g · kg^-1）, SM ＋ DOO （ 10 g · kg^-1 ＋ 0. 5 ml · kg^-1）. Rats were pretreated with homologous drug for 7 days and then subjec- ted to 30 rain of ischemia followed by 180 rain of reperfusion. Electrocardiogram （ECG） and heart rate were moni- tored and recorded continuously. At the end of reperfusion, blood samples were collected to determine the serum levels of creatine kinase-MB （CK-MB） and lactate dehydrogenase （LDH）. Hearts were harvested to assess heart- body rate, infarct size and histopathological changes as well. Maximum and minimum effective points were deter- mined by measuring indicators associate with myocardial injury at different time-points of reperfusion （Smin, 15min, 30min, 45rain, 60min, 120min, 180min）. The potential therapeutic mechanism of SM and SM ＋ DOO were carried out by detecting superoxide dismutase （SOD）, malondialdehyde （MDA）, tumor necrosis factor-alpha （TNF-alpha） and interleukin 6 （IL-6）. Results The results showed SM and DO can ameliorate cardiac function respectively, and this cardioprotective effect was further strengthened by their combinations. Among all the combi- nations, SM ＋ DOO showed predominant potential to improve ECG and heart rate, reduce heart-body rate （28.5% ＋ 1.4% , P 〈 0.01 vs model） and myocardial infarct size （ 20.96% ＋ 1.61% , P 〈 0.01 vs model, P 〈 0.05 vs SM） , attenuate histopathological damage, decrease the levels of CK-MB and LDH （P 〈 0.01 vs model, P 〈 0.05 vs SM）. The maximum effective points of SM and SM ＋ DOO were 15min and 30rain respectively, and the minimum effective points of them were 180rain. In reducing serum level of MDA, TNF-alpha, IL-6 and increasing SOD activ- ity, SM ＋ DOO was similar to SM. Conclusion The results of this study indicated that SM ＋ DOO have combined effects that are highly effective than single pretreatment against myocardial ischemie reperfusion injury in rats. The possible mechanism of SM and DO were likely through its anti-oxidant and anti-inflammatory properties, and thus may be an effective and promising medicine for both prophylaxis and treatment of ischemic heart disease.
基金This work supported by the National Natural Science Foundation of China (81470432) and Natural Science Foundation of Anhui Province Education Department (KJ2016A357).
文摘OBJECTIVE In this study we explored the role of Epac1-Rap1 pathway in the acute myocardial ischemia/reperfusion injury(MIRI) in vitro and in vivo.METHODS An acute myocardial ischemia/reperfusion injury model was established by the ligation of left anterior descending coronary.Myocardial architecture,fibers and apoptosis was evaluated by the Masson trichrome staining,Sirius red staining and TUNEL assay.H9c2 cells were subjected to hypoxia for 5 h followed by 1-h reoxygen.ation in vitro.Cell viability was measured by MTT assay and cellular injury was evaluated by measuring the release of lactate dehydrogenase(LDH).Western blot,real-time PCR and immunofluorescence were used to detect the expressions of Epac1 and relative downstream molecules.RESULTS Myocardial IR-induced cardiac apoptosis and accumulation of Epac1 and Rap1 in rat IR injury model.Direct Epac activation by 8-CPT(8-(4-chlorophenylthio)-2′-O-methyl-cAMP) exacerbated cardiomyocyte death and dysfunction following hypoxia-reoxygenation(H/R),selective activation of Epac in response to H/R was evident which enriched for cytosolic/membrane proteins and mRNA.Harmacological inhibitor of Epac(ESI-09) significantly ameliorated myocardial injury with the decline of Epac expression.Epac inhibitor and agonist studies also implicated the effect of Rap1,which is downstream of Epac in this pathway.The expression of Rap1 elevated when activated by Epac agonist and was blocked by Epac inhibitor.The same result was true for myocyte CaMK-II and intracellular calcium ions activation.Moreover,ESI-09 also increased ERK1/2 phosphorylation.CONCLUSION Our study reveal that Epac1/Rap1 signaling pathway is involved in the pathogenesis of myocardial I/R injury in rats,which provides evidence on the development of therapeutic strategies target this pathway for myocardial I/R injury.
基金Fund of Dean of Huachuang Institute of Areca Research-Hainan(HCBL2020YZ-012)。
文摘The morbidity and mortality of cardiovascular diseases are very high,which has attracted more and more attention all over the world.Common treatment methods for clinical treatment of acute myocardial infarction include direct percutaneous coronary intervention and coronary artery bypass grafting,which can quickly restore blocked coronary blood flow and reduce the infarct size.However,the inevitable ischemia/reperfusion injury will occur during the recovery of coronary blood flow,its pathological mechanism is complicated,and the Western medicine countermeasures are very limited.Among the current drugs for the treatment of cardiovascular diseases,traditional Chinese medicine has become a research hotspot due to its multiple targets,safety,and low side effects.Ginger is the fresh rhizome of Zingiber officinale Rosc.,a perennial herbaceous plant in the ginger family.It is a dual-purpose resource of medicine and food.Ginger has the functions of relieving the appearance and dispelling cold,warming up and relieving vomiting,resolving phlegm and relieving cough,and relieving fish and crab poison.The chemical components of ginger mainly include volatile oil,gingerol,diphenylheptane,etc..Among them,6-gingerol,as the main active component of gingerols,has obvious pharmacological effects in myocardial protection,anti-oxidation,anti-inflammatory,etc..Studies have shown that 6-gingerol protects myocardium mainly through anti-oxidative stress,anti-inflammatory,inhibiting cell apoptosis,and preventing calcium influx.①Anti-oxidative stress:oxidative stress is a state where oxidation and anti-oxidation in the body are out of balance,and it is also an important factor leading to myocardial damage.Many studies have confirmed that 6-gingerol has an antioxidant effect,and it is considered a natural antioxidant.6-gingerol can significantly reduce the degree of oxidative stress and the level of reactive oxygen species caused by cardiomyocyte damage,and has a significant cardioprotective effect.②Anti-inflammatory:inflammation can cause substantial cell damage and organ dysfunction,which is another important cause of myocardial damage.6-gingerol can reduce the levels of inflammatory factors such as interleukin-6,interleukin-1β,and tumor necrosis factor-αin cardiomyocytes,and at the same time inhibit the TLR4/NF-κB signaling pathway,an important regulatory pathway of inflammation,showing that it may improve myocardial damage through anti-inflammatory effects.③Inhibition of apoptosis:apoptosis is a complex and orderly process in the autonomous biochemical process of cells,and one of the main mechanisms of myocardial injury.This process can be roughly divided into three pathways:mitochondria,endoplasmic reticulum,and death receptors.Among them,the mitochondrial pathway plays an important role,and Bcl-2 and Bax located upstream of this pathway can regulate the entire process of cell apoptosis by regulating the permeability of the mitochondrial membrane.Studies have found that the preventive application of 6-gingerol can reduce cell damage,reduce the number of apoptotic cells,reduce the activity of Bax and caspase-3,and increase the expression of Bcl-2.Therefore,6-gingerol pretreatment can reduce the damage of cardiomyocytes,and its mechanism may be related to the inhibition of apoptosis.④Prevent calcium influx:calcium overload is involved in the pathogenesis of myocardial ischemic injury,which may be related to excessive contracture,arrhythmia,and mitochondrial Ca2+accumulation that impairs myocardial function.6-gingerol inhibits the increase of intracellular Ca2+concentration by inhibiting L-type calcium current,thereby reducing extracellular Ca2+influx,thereby avoiding calcium overload and playing a cardioprotective effect.In summary,6-gingerol can effectively treat and improve myocardial ischemia/reperfusion injury,and it has great development potential in the fields of medicine and health products.
文摘Myocardial infarction resulting from coronary atherosclerosis is the leading cause of death in modern soci- ety. Reperfusion is an essential treatment to salvage ischemia myocardium from necrosis, while it also leads to addi- tional damage. Therefore, exploring effective medicines to protect the heart from post-ischemic injury is one of the major objectives of cardiovascular research. Berbamine is a nature compound of bisbenzylisochinoline alkaloids from Barberry. We found that it displays positive inotropic and lusitropic effects at lower concentrations by increasing myofilament Ca2＋ sensitivity via a PKCe-dependent signaling pathway. Moreover, berbamine preconditioning con- fers cardioprotection against ischemia/reperfusion （I/R） injury by attenuating the Ca2＋ overloading and preventing the calpain activation through the activating of PI3K-Akt-GSK3β pathway and subsequently opening of the mitoKATP channel. Furthermore, we demonstrate that berbamine postconditioning conferred the cardioprotective effect against I/R injury by the regulation of autophagy. These findings reveal new roles and mechanisms of berbamine in the heart and cardioprotection against I/R injury.
