The Study On The Protective Mechanisms Of Sphingosylphosphorylcholine Secreted By Vascμlar Endothelium Cells On Cardiomyocytes Exposed To Hypoxia

Ischemic heart disease,such as acute myocardial infarction,is one of the most fatal diseases in the world.Most myocardial infarctions are caused by coronary artery obstruction leading to local ischemia in the left ventricle,triggering the occurrence of myocardial cell necrosis and inflammation,followed by fibrosis and hyperplasia,accompanied by poor ventricular remodeling,and finally leading to heart failure.Early intervention resulted in a significant reduction in mortality,but the dead heart cells were not renewed and patients were treated with heart defects.Therefore,it is of great significance to investigate the molecular mechanism of regulating the death of myocardial cells from the important factors affecting the death of myocardial cells to intervene the regulation of myocardial plasticity after myocardial infarction.The interaction between two cells has long been an area of intense interest in cell biology.Vascular endothelial cells（VECs）and cardiomyocytes（MCs）are physiologically similar and can communicate through paracrine signals and direct cell-cell contact.Evidence has shown that VECs and MCs interact in the process of myocardial ischemia and even post-ischemia remodeling,and it has been found that some parsecretory factors,including cytokines,are involved in the protective effect of VEC on hypoxic myocardium,but more other factors released by VEC need to be further studied.Sphingosine phosphoric acid choline（Sphingosylphosphorylcholine,SPC）is a blood,heart,blood vessels,brain and the immune system in the widespread sphingomyelin,intermediate metabolites are also present in the biological membrane and cytoplasm.Our previous studies have found that SPC is a key factor involved in cardiovascular diseases and can inhibit the apoptosis of hypoxic cardiomyocytes,but the source of SPC is not clear yet,and whether SPC is released through endothelium to participate in the regulation of myocardium still needs further study.In this study,an in vitro model of endothelial myocardium protected by hypoxia was established to detect the effects of hypoxia on the release of SPC by myocardium and endothelial cells.It was found that hypoxia mainly promoted the release of SPC by endothelial cells.In addition,exosome inhibitors can inhibit the release of SPC by endothelial cells and destroy the protective effect of endothelial cells on cardiomyocytes.These results suggest that endothelial cells may release SPC in the way of exosomes to protect the apoptosis of hypoxic cardiomyocytes.On the basis of previous studies,we fluorescously labeled SPC,observed that SPC could enter cardiomyocytes,and found that SPC could protect hypoxic myocardium by regulating NR4A2,which may be related to the promotion of NR4A2 to the expression of mitochondrial selective autophagy receptor OPTN.At present,there are few reports on the regulation of SPC release.High fat and hypoxia are both important factors causing heart disease,but whether high fat can induce VEC to release SPC has not been reported.Our study found that high lipid palmitic acid（PA）also promoted the release of SPC in VEC.Moreover,both PA and SPC promoted the spotty aggregation of NR4A2 in endothelial cells,suggesting that PA may play a role through SPC.In addition,the expression and nuclear displacement of NR4A2 in PA treated cardiomyocytes were consistent with that in hypoxia condition,but SPC treated cardiomyocytes induced by PA promoted the apoptosis of cardiomyocytes induced by PA,the specific mechanism remains to be further studied.The present study further examined the correlation between the changes of serum SPC and endothelial release of SPC in patients with acute heart infarction and obese patients.Serum SPC levels were found to be elevated in obese patients,but significantly decreased in patients with acute heart infarction.PCR results showed that it may be related to the elevated level of autotoxin which promotes the hydrolysis of SPC in the blood of patients with acute heart infarction.Therefore,this study proposed that both hypoxia and PA can promote the release of SPC in endothelial cells,and the release may be in the form of exosomes,and the released SPC can enter cardiomyocytes and play different roles in different cell models.This study helps to clarify the molecular mechanism of endothelial regulation of myocardial cell apoptosis and autophagy,which is of great significance for the intervention of cardiac remodeling after myocardial infarction.