The Effect Of Proteoglycan 4 On Cardiac Function After Myocardial Infarction

Background:Cardiovascular disease(CVD)is the leading cause of death.The mechanism of cardiac remodeling after myocardial infarction is complex and involves cardiac fibrosis and cardiomyocytes death.Recent research indicated that proteoglycan,as an important component of extracellular matrix,has been shown to be involved in regulating fibrosis in various tissues,but its role in ventricular remodeling after myocardial infarction remains to be clarified.Proteoglycans are composed of core protein and glycosaminoglycans chains such as chondroitin sulfate and keratan sulfate,and its family member proteoglycan 4(PRG4)is highly expressed in mammalian hearts.The purpose of this study is to explore the role and mechanism of PRG4 in ventricular remodeling after myocardial infarction,and to provide a scientific basis for the development of new therapeutic targetsMethods and Results:The model of mouse myocardial infarction was developed through the ligation of anterior descending branch of left coronary artery.PRG4 was highly expressed in the myocardium of patients with advanced heart failure,as well as in mouse models of myocardial infarction,which was detected by immunohistochemistry,western blot,and fluorescent quantitative PCR.After myocardial infarction,PRG4 expression in mouse heart tissues significantly increased,especially the infarct area.PRG4 expression was highest at 3 day after myocardial infarction in mice,and then gradually decreased,but it was still significantly higher than that in the sham group.We constructed PRG4-shRNA adenovirus,and mice received local myocardial injection of PRG4-shRNA adenovirus immediately after ligation of anterior descending branch of left coronary artery.PRG4 knockdown in mouse heart improved cardiac function in mice at day 7 after myocardial infarction.Hypoxia or H2O2 stimulation of neonatal mouse cardiomyocytes promoted cardiomyocytes apoptosis.While PRG4 significantly decreased in cardiomyocytes,PRG4 in the supernatant increased.Scratch test and CCK8 test were conducted.PRG4 knockdown in mouse cardiac fibroblast inhibited fibroblast migration and proliferation.Cardiac fibroblast PRG4 knockdown significantly inhibited the expression of inflammatory factor IL-1β and significantly inhibited TGF-β mediated α-SMA expression and collagen synthesis,suggesting that cardiac fibroblast PRG4 knockdown inhibited the activation and transdifferentiation of fibroblasts to myofibroblasts.Conclusion:After myocardial infarction,the expression of PRG4 significantly increased and was positively correlated with abnormal activation of fibroblasts;PRG4 knockdown suppressed abnormal activation of fibroblasts,reduced the release of proinflammatory factors,and relieved ventricular remodeling.