中山大学学报（医学科学版）2025，Vol.46Issue(2)：275-283,9.
α-酮戊二酸介导异柠檬酸脱氢酶3A发挥抑制心肌细胞肥大的作用
IDH3A Inhibits Cardiomyocyte Hypertrophy via Elevating α-Ketoglutarate Level
摘要
Abstract
[Objective]To investigate the regulatory effect and potential mechanisms of isocitrate dehydrogenase 3A(IDH3A)on cardiomyocyte hypertrophy.[Methods]The expression of IDH3A in the myocardium of healthy volunteers(n=10)and patients with heart failure(HF)(n=10),and in the myocardium of mice subjected to transverse aortic constriction(TAC)surgery and sham operation,as well as in phenylephrine(PE)-induced neonatal rat ventricular cardiomyocytes(NRVCs),was assessed by real-time quantitative polymerase chain reaction(RT-qPCR)and Western blot assay.The effect of adenovirus-mediated overexpression of IDH3A on the expression of hypertrophy-related genes in PE-induced NRVCs was also evaluated.The effect of IDH3A on NRVCs area was examined by phalloidin staining assay.A mutant of IDH3A with abolished enzymatic activity,IDH3A_D208A,was generated through site-directed mutagenesis.The impact of this IDH3A mutant on the hypertrophic phenotype,ATP and ROS levels in NRVCs was evaluated to investigate whether the regulatory role of IDH3A in cardiomyocyte hypertrophy was dependent on its enzymatic activity.The effect of exogenous α-ketoglutaric acid(AKG)on cardiomyocyte hypertrophy was also detected by Western blot and phalloidin staining assay,respectively.[Results]IDH3A was significantly decreased in the myocardium of HF patients,in the myocardium of TAC-operated mice,and in PE-induced NRVCs(P=0.005 2,P=0.026 6,P=0.041 3 and P=0.006 6,respectively).Overexpression of IDH3A markedly suppressed the expression of hypertrophy-related genes and the increase of cell size of PE-induced NRVCs(P<0.000 1,P=0.000 1 and P=0.000 2,respectively).The ATP and ROS analysis indicated that IDH3A inhibited the increases of ATP and ROS levels in PE-induced NRVCs(P=0.001 2 and P<0.000 1,respectively),whereas the enzymatically inactive IDH3A mutant lacked this effect.Exogenous AKG provision could,but overexpression of IDH3A mutant failed to suppress PE-induced NRVCs hypertrophy.[Conclusion]IDH3A inhibits cardiomyocyte hypertrophy via elevating AKG level,providing scientific evidence for study on IDH3A-based treatment of cardiac hypertrophy.关键词
心肌肥厚/异柠檬酸脱氢酶3A/α-酮戊二酸/心肌细胞/线粒体Key words
cardiac hypertrophy/isocitrate dehydrogenase 3A/α-ketoglutarate/cardiomyocytes/mitochondria分类
医药卫生引用本文复制引用
伍华燕,温艺红,赵亨利,高原,周川孟,王娅,朱杰宁,单志新..α-酮戊二酸介导异柠檬酸脱氢酶3A发挥抑制心肌细胞肥大的作用[J].中山大学学报（医学科学版）,2025,46(2):275-283,9.基金项目
国家自然科学基金(82470253) （82470253）
广东省自然科学基金(2022A1515012522,2022A1515012175) （2022A1515012522,2022A1515012175）
