Study On The Function And Mechanism Of Sphingosylphosphorylcholine In Cardiomyocytes Injury Induced By High Glucose

Diabetic cardiomyopathy is the leading cause of heart failure and death in diabetic patients.Diabetes includes type I and type II diabetes.Among them,hyperglycemia is the main pathological factor of cardiomyopathy associated with advanced type 1 diabetes.Studies have shown that hyperglycemia can damage the mitochondrial function of cardiomyocytes,making them a major source of reactive oxygen species(ROS)and pro-apoptotic factors,ultimately leading to cardiomyocyte death.Since cardiomyocytes occupy an important position in the heart,mitochondrial damage in cardiomyocytes is an important pathophysiological basis for diabetic cardiomyopathy.Current studies have found that hyperglycemia mainly causes myocardial mitochondrial damage by promoting the production of advanced glycation end products(AGEs)and abnormal lipid metabolism.However,there is still a lack of effective intervention methods,and more molecular mechanisms of diabetic cardiomyopathy caused by hyperglycemia damage myocardial mitochondria need to be further studied.Our previous study found that sphingosylphosphorylcholine(SPC)can protect cardiomyocytes against hypoxia-induced apoptosis and is involved in mitochondria-related pathways,but whether it can protect cardiomyocytes from high glucose-induced injury has not been reported.Here,we confirmed the protective effect of SPC on high glucose-induced cardiomyocyte apoptosis by detecting the changes of apoptosis indicators firstly,then,we detected the changes of mitochondrial membrane potential(MMP),ATP and ROS levels,it was found that that SPC can alleviate high glucose-induced MMP loss and ROS release in cardiomyocytes,and restore their mitochondrial function.Using gene chip and Western blot,it was screened and verified that SPC could promote the activation and expression of JNK and GATAD1 in H9C2 cells.Using siRNA to verify that JNK and transcription factor GATAD1 play an important role in the protection of SPC from high glucose-induced damage to H9C2 cells.Furthermore,we found that JNK participates in the promotion of mitophagy of SPC to maintain mitochondrial function;while GATAD1 restores mitochondrial function through mitochondrial regeneration by regulating the transcription of PGC-1α and its downstream factors PPAR-α and ERR.Through the verification of the relationship between JNK and GATAD1,it was finally found that JNK can promote the expression of GATAD1 and inhibit its phosphorylation to promote its entry into the nucleus.So,it is speculated that JNK indirectly regulates the post-translational modification and nuclear localization of GATAD1.Therefore,SPC promotes JNK-related mitophagy on the one hand,and JNK/GATAD1/PGC-lα-related mitochondrial regeneration on the other hand,maintains mitochondrial homeostasis from two aspects,and alleviates the damage to cardiomyocytes caused by high-glucose environment.This paper preliminarily explores part of the mechanism by which SPC protects cardiomyocytes from high glucose-induced injury,and the results of this study will provide a theoretical basis for the treatment of diabetic cardiomyopathy.