The Regulation Mechanism Of Trim44 Involved In Isoproterenol-induced Myocardial Remodeling

BackgroundCardiac hypertrophy increases mortality from a variety of cardiovascular diseases,it was found that Trim44 was associated with atrial fibrillation,heart failure and other cardiovascular diseases,and Trim44 is involved in the damage process of human primary myocardial cells.However,the effects of Trim44 on heart morphology and function,especially on cardiac hypertrophy and HF pathological process,are still unclear,and related animal model studies are lacking.Therefore,in this paper,a rat model of myocardial tissue-specific Trim44 knockout was established to explore the effect of Trim44 on myocardial remodeling and it provides clinical significance for the prevention and treatment of cardiovascular diseasesMethods1.Conditional and myocardial tissue-specific Trim44 knockout rats were established by CRISPR/Cas9 technique.2.Western blotting,immunofluorescence,immunohistochemistry and other techniques were used to verify the expression and localization of Trim44 in wild-type and knockout rat cardiomyocytes.3.Ultrasonic imaging and histopathological techniques were used to observe the effects of Trim44 knockout on the structural morphology and function of the rat heart.4.Western blot and in vitro cell validation techniques were used to detect the activation of AKT-P70S6K-GSK3β-mTOR.Results1.Trim44 is mainly located in the cytoplasm of cardiomyocytes.In normal rat cardiomyocytes,the expression level of Trim44 is high at 3 to 5 months of age.However,in the pathological condition of cardiac hypertrophy,the expression level was significantly increased.2.Cardiac tissue specific Trim44 knockout rats showed morphological changes from 3 months of age to 5 months of age,with ventricular wall thinning and ventricular lumen smaller,stroke output decreased,left ventricular weight decreased,and delayed development of cardiac hypertrophy as a whole.3.Deletion of Trim44 significantly inhibited the pathological development of myocardial hypertrophy induced by ISO in rats,and the changes of overall cardiac structure and function,histopathology and molecular markers were significantly improved.4.Deletion of Trim44 significantly inhibited ISO-induced abnormal activation of AKTP70S6K-GSK3β-mTOR signaling pathway in rat myocardial tissue;AKT inhibitors can significantly inhibit the activation of the above signaling pathways in H9c2 cell lines with Trim44 overexpression,and the changes of cell morphology and molecular markers are also improved.ConclusionTrim44 may be involved in the regulation of ISO-induced pathological process of cardiac hypertrophy through AKT-P70S6K-GSK3β-mTOR signaling pathway.This study further clarified the biological role of Trim44,providing theoretical support and clues for the treatment of clinical cardiac hypertrophy,heart failure and other cardiovascular diseases.