Study On The Relationship Of LSD1 With Lipid Metabolism And Oxidative Stress In The Pathogenic Mechanisms Of Pathological Cardiac Hypertrophy

Background:A series of cascades are activated in the process of cardiac hypertrophy:the content of cardiac contractile proteins,changes in energy metabolism,and oxidative stress.In normal hearts,cardiomyocytes are mainly oxidized by fatty acids to meet the energy requirements in the body,while during cardiac hypertrophy,the metabolism of the heart is more dependent on glucose,amino acids than fatty acids as the main source of energy.Oxidative stress caused by cardiac hypertrophy can further lead to cardiac remodeling and ultimately to heart failure.Therefore,understanding the role of fatty acid oxidation and oxidative stress in cardiac hypertrophy can help us improve our current diagnosis and treatment strategies for cardiac hypertrophy.However,previous studies have focused on their independent effects,ignoring the potential interactions of energy metabolism and epigenetics in cardioprotection^[2].In this study,isoproterenol?ISO?and LSD1 specific inhibitor OG-L002 were used to construct rat cardiac hypertrophy model.The role of LSD1 on oxidative stress and lipid metabolism in pathological cardiac hypertrophy was explored.Objective:1.To investigate the relationship between histone demethylase?LSD1?and the change of fatty acid metabolism in the pathogenic mechanisms of pathological cardiac hypertrophy induced by continuously activating?-adrenergic receptor byISO.2.Preliminary explore the relationship between histone demethylase?LSD1?and the oxidative stress related protein Nrf2 expression in the ISO-induced pathogenic mechanisms of pathological cardiac hypertrophy.Methods:Select healthy male Sprague Dawley?SD?rats,weighing 120¹50 g,fed with SPF method.The rats were fed with free diet,water intake and natural circadian light.The rats were randomly divided into three groups:control group,ISO group and OG-L002 group,with six rats in each group.Various experimental methods such as heart-weight ratio,echocardiography,real-time quantitativePCR,hematoxylin-eosin staining,Western Blot,immunohistochemical detection,blood metabolomics and so on were used for detection:1.The expression of cardiac function,myocardial hypertrophy phenotype,hypertrophic factor,LSD1 and its downstream proteins in rats of each group;2.The changes of lipid metabolism and the expression of AGPS genes related with lipid metabolism were detected by blood metabolomics in each group.3.The expression of oxidative stress related proteins and genes in each group.Results:1.Establishment of rat model of myocardial hypertrophy and changes of LSD1expression in rat myocardiumCompared with the Control group,the ISO group and the OG-L002 group showed obvious hypertrophy in the heart:left ventricular wall thickness and left ventricular mass increased significantly,left ventricular end diastolic diameter decreased,ejection fraction and left ventricular short axis shortening rate were decreased.The heart and the heart-to-weight ratio increased significantly.The cross-sectional area of cardiomyocytes stained with hematoxylin-eosin was significantly increased.The expression of LSD1 protein was significantly decreased by immunohistochemistry and the expression of downstream protein was increased.LSD1 protein and mRNA expression decreased,LSD1 downstream histone protein and mRNA expression increased;myocardial tissue myosin light chain-2v,?-type myoglobin heavy chain,atrial natriuretic peptide protein and mRNA expression Elevated?n=6,*P<0.05,**P<0.01,***P<0.001?.2.Changes of lipid metabolism and related genes in rats with cardiac hypertrophy:The blood metabolome test showed that the fatty acid degradation in the ISO group and the OG-L002 group was reduced compared with the Control group.Western Blot and real-time quantitative PCR showed that the expression of AGPS protein and mRNA increased in both ISO and OG-L002 groups compared with those in Control group?n=6,**P<0.01?.3.Changes of oxidative stress in rats with myocardial hypertrophyChanges of oxidative stress-related genes:Western Blot and real-time quantitative PCR results showed that the expression of Nrf2 protein and mRNA decreased in ISO group and OG-L002 group,while the expression of Keap-1 protein and mRNA increased in control group?n=6,*P<0.05,**P<0.01,***P<0.001?.Conclusion:Continuously activating?-adrenergic receptor by ISO may lead to cardiac hypertrophy through increasing histone methylation level.In the pathogenic mechanisms of pathological cardiac hypertrophy by ISO or LSD1 inhibitor,abnormal energy metabolism occurred,fatty acid degradation reduced,the expression of AGPS gene increased and Nrf2 decreased.Therefore the lipid metabolic disorders and the change in oxidative stress level may have a definite relationship with LSD1 level in the development of pathological cardiac hypertrophy.