Study On The Mechanism Of ESM-1 Reducing NO Production In Hypertensive Cardiac Hypertrophy By Regulating PRMT1-ADMA

Objective:Hypertension is the most common risk factor for cardiovascular and cerebrovascular diseases,which greatly threatens human health.Left ventricular myocardial hypertrophy(LVH)is one of the most common target organ damages in hypertension and an independent risk factor for adverse cardiovascular and cerebrovascular events such as cardiac insufficiency,arrhythmia,stroke and sudden death.More and more studies have found that long-term hemodynamic load is not the only factor that forms LVH.Endothelial cell specific molecule-1(ESM-1)is a dermatan sulfate protein isolated from endothelial cells.ESM-1 has a very wide range of biological activities and it is considered involved in the inflammatory process and tumorigenesis.It is also considered a new marker of endothelial dysfunction.Some studies have reported that the expression level of ESM-1 in serum of patients with hypertensive myocardial hypertrophy is significantly increased,suggesting that ESM-1 may be involved in the occurrence of hypertensive myocardial hypertrophy,but the specific mechanism is not clear.Therefore,This study analyzed the relationship between ESM-1 and hypertensive myocardial hypertrophy in a rat model of hypertensive myocardial hypertrophy by molecular biology,lentiviral transfection,and chronic animal experiments.This topic explores the role of Type 1 protein arginine methyltransferase-asymmetric dimethylarginine(PRMT1-ADMA)metabolic axis and nitric oxide synthase / nitric oxide Nitrogen(NOS / NO)system in ESM-1-induced hypertensive myocardial hypertrophy,and also clarifies the role and significance of ESM-1 in hypertensive myocardial hypertrophy,and clarifies the mechanism by which ESM-1 causes hypertensive myocardial hypertrophy by regulating the PRMT1-ADMA metabolic axis.The study provides important theoretical content and provides important guiding significance for the prevention and treatment of hypertensive myocardial hypertrophy.Methods:First,the study was divided into a normal blood pressure WKY rat control group and a spontaneously hypertensive group.The cardiac mass and body weight were measured,and the ratio of cardiac mass to body weight was calculated.HE tissue staining was used to observe changes in cardiac muscle cell size,and ELISA was used to detect NO content in cardiac tissue.Western Blot was used to detect the expression of ESM-1 protein in cardiac tissue,and to clarify the changes of ESM-1 and NO production in the heart of hypertensive myocardial hypertrophy rats.Then spontaneously hypertensive rats(SHR)and normal-hypertensive WHY rats were injected with ESM-1 interference and over-expressing lentivirus in the heart,respectively.By measuring cardiac weight ratio and molecular markers of cardiac cell hypertrophy,Western Blot was used to detect rats The expression of ESM-1,PRMT1,DDAH1,DDAH2,and NOS isoforms in cardiac tissues.ELISA was used to detect the amount of NO and ADMA content in cardiac tissues to determine whether ESM-1 inhibits the production of NO in myocardial cells through ADMA accumulation,thereby participating in The occurrence of blood pressure and myocardial hypertrophy.Finally,WKY rats were divided into EMS-1 overexpression group and control lentiviral treatment group.PRMT1 inhibitor(AMI-1)was injected intraperitoneally at the second week of lentivirus injection.ELISA was used to detect the content of NO and ADMA in cardiac tissues,and to determine whether ESM1 could affect the PRMT1-ADMA axis,regulate the content of ADMA in cardiomyocytes and reduce the production of NO,thereby participating in the development of myocardial hypertrophy in hypertension.Results:1.The expression of ESM-1 in cardiac tissue of hypertensive myocardial hypertrophy rats increased,while the production of NO decreased accordingly,suggesting that ESM-1 participates in hypertensive myocardial hypertrophy by acting on NOS / NO system.2.After SHR cardiac tissue interferes with ESM-1 expression,it can reduce the content of ADMA in the cells and increase the production of NO in myocardial cells.The NOS subtype has no significant change after interfering with ESM-1,which suggests that ADMA plays an important role in ESM-1 caused abnormal NO production in cardiomyocytes.3.After overexpression of ESM-1 in myocardial cells of WKY rats,the intracellular ADMA content increased and NO production decreased,and the molecular markers of myocardial hypertrophy in rats increased significantly,while NOS isoforms were not apparent after ESM-1 overexpression change.4.After ESM-1 was overexpressed in WKY rat cardiomyocytes,PRMT1 expression was up-regulated;after SHR cardiac tissue interfered with ESM-1,PRMT1 expression was down-regulated.There was no significant difference in the expression of DDAH1 and DDAH2 between the groups.5.Intraperitoneal injection of PRMT1 inhibitor AMI-1 can reduce the increase of ADMA content in myocardial cells caused by overexpression of ESM-1 in WKY rats and increase the production of NO in cardiac tissues.It shows that ESM-1 affects the PRMT1-ADMA axis to regulate NO production and participate in the pathophysiology of hypertension myocardial hypertrophy.Conclusion:ESM-1 regulates the metabolic axis of PRMT1-ADMA to cause ADMA accumulation,inhibit NO production,and participate in the pathophysiology of hypertensive myocardial hypertrophy.