| Ischemic heart disease is an illness in which blood vessels are stenotic or blocked due to coronary atherosclerosis,causing cardiac ischemia and hypoxia in downstream tissues.Among them,hypoxia is a pathological feature existing in a variety of cardiovascular diseases,which is important in mediating cardiac remodeling and various biological functions of cardiac cells.Hypoxia can induce apoptosis in heart.At present,most studies focus on the apoptosis of cardiomyocytes,and there are few reports about cardiac fibroblast(CF).However,CF is a key factor in myocardial repair,which can produce collagen and increase the tensile strength of heart.Damage to fibrotic repair results in reduced tensile strength of the heart wall.However,the persistence of CF after injury can lead to infarction,adverse cardiac remodeling and cardiac hypertrophy,arrhythmia,heart failure.Therefore,the search for mechanisms to inhibit CF apoptosis in mature stage can provide theoretical basis and molecular targets for post-injury repair.Calmodulin(CaM)is a 17 KDa calcium-binding protein that widely exit in eukaryotic cells.CaM can regulate excitatory-contraction coupling and participate in arrhythmia-related signal transduction by binding to many target proteins including kinases,phosphatases,ion channels and transcription factors,etc.;and overactivation of CaM leads to heart failure,cardiac hypertrophy.Therefore,CaM is essential in the human,especially in the heart.However,there are few studies on the role of CaM in CF,and the mechanism of CaM under hypoxic conditions in CF are not clear.In view of the broad spectrum anti-apoptotic function of SPC,it can also promote autophagy;previous studies in our laboratory found that SPC can inhibit apoptosis by promoting autophagy in ischemic cardiomyocytes.and CaM is a receptor for SPC.Therefore,we intend to study on the molecular mechanism of CaM in hypoxia-induced CF autophagy and apoptosis and whether SPC has the same effect as cardiomyocytes in CF.The results showed that hypoxia treatment induced apoptosis in CF,and treatment with SPC could promote CF autophagy,which occurred in autophagy flux.At the same time,SPC has the function of inhibiting apoptosis in CF,indicating that SPC may inhibit the apoptosis in CF by promoting the autophagy and preventing cells from entering the apoptotic pathway.An experimental system for interfering with CaM expression was established using siRNA interference technology.It was found that interfering with CaM expression or inhibiting its function can increase autophagy in CF and inhibit its apoptosis,indicating that CaM plays an important role in autophagy and apoptosis;the function of SPC and the CaM inhibitor trifluoperazine(TFP)is similar,and the addition of SPC and TFP has a superimposed effect;while SPC and Ca2+-ATPase inhibitors(which can raise intracellular Ca2+ concentration)have opposite effects,indicating that SPC participates in CF autophagy and apoptosis through CaM.Further studies have found that hypoxic treatment can increase the phosphorylation levels of p38 and STAT3 in CF,and SPC treatment of CF can inhibit this process,with the inhibition of apoptosis.The above results were confirmed by parallel experiments with the p38 inhibitor SB 253080,the stat3 inhibitor stattic,and the STAT3 agonist TFA.This indicates that SPC can inhibit hypoxia-induced apoptosis by inhibiting phosphorylation of p38/STAT3.In addition,phosphorylation levels of p38 and STAT3 also decreased after the inhibition of CaM.Taken together,we thought that SPC may regulate phosphorylation of p38 and STAT3 through its receptor CaM,thereby inhibiting CF apoptosis under ischemic conditions either directly or by enhancing autophagy.The homogeneity of SPC on CF and cardiomyocytes provides materials for study and future treatment of ischemic cardiovascular diseases.SPC has the functions of enhancing autophagy and inhibiting apoptosis in CF.This study provide molecular mechanism of cardiac remodeling after cardiovascular disease. |
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