P66Shc Deletion Ameliorates Oxidative Stress and Cardiac Dysfunction in Pressure Overload-Induced Heart Failure

Abstract

p66Shc is a redox enzyme that plays an important role in the response of oxidative stress and the p53-dependent apoptosis. The expression level of p66Shc has a negative correlation with the resistance of oxidative stress in vivo and in vitro. We aim to demonstrate the function of p66Shc in pressure overload-induced heart failure. The pressure overload-induced heart failure was induced in mice by transverse aortic constriction (TAC). Cardiac dysfunction was shown by transthoracic echocardiography. Western blot was used to check the protein levels of phosphodiesterase type 5 (PDE5) and ventricular oxidative stress markers. Superoxide dismutase (SOD) mimetic M40401 and PDE5 inhibitor sildenafil were used in the treatment of mice. The deletion of p66Shc attenuated cardiac dysfunction and oxidative stress in pressure overload-induced heart failure. p66Shc deletion also decreased the expression of ventricular oxidative stress markers and enhanced PKG signaling by promoting the expression of PDE5. M40401 and sildenafil attenuated the TAC-induced cardiac dysfunction and oxidative stress in p66Shc overexpression mice. Our findings suggest that p66Shc participates in the regulation of cardiac dysfunction and oxidative stress in TAC-derived pressure overload-induced heart failure in mice, and SOD and PDE5 are molecules downstream of p66Shc in this regulatory process.