MARCH5 Promotes Cardiac Hypertrophy by Regulating Akt/mTOR/Gsk-3β/GATA4 Signalling Pathway

This study aims to elucidate the role of MARCH5 in cardiac hypertrophy, thereby providing a theoretical foundation for novel therapeutic strategies for cardiac hypertrophy and heart failure. The expression of MARCH5 in cardiac hypertrophy models was assessed using immunohistochemistry, western blot (WB) and RT-qPCR. Gain- and loss-of-function experiments of MARCH5 in cardiac hypertrophy were conducted both in vitro and in vivo. WB, RT-qPCR, co-immunoprecipitation (CoIP), immunohistochemistry and immunofluorescence were performed to investigate the molecular mechanisms of MARCH5. MARCH5 expression was upregulated in hypertrophied myocardium. Ang II stimulation resulted in increased expression of MYH7, BNP and cardiomyocyte area. These effects were aggravated by MARCH5 overexpression but antagonised by MARCH5 knockdown. MARCH5 heterozygous (MARCH5^+/-) mice subjected to transverse aortic constriction (TAC) demonstrated alleviation of cardiac hypertrophy and improvement in cardiac function, whereas MARCH5 overexpression aggravated hypertrophy and cardiac dysfunction. Mechanistic studies indicated that MARCH5 directly interacted with Akt, enhancing the phosphorylation of Akt, mTOR and Gsk3β, thereby increasing GATA4 expression and aggravating cardiac hypertrophy. Our findings suggest that MARCH5 participates in the pathological cardiac hypertrophy by regulating the Akt/mTOR/Gsk-3β/GATA4 pathway, positioning it as a promising therapeutic target for cardiac hypertrophy.