β‐Adrenergic Receptor (β‐AR)‐Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling are Modulated by Exogenous Ubiquitin

Abstract

β‐AR stimulation increases levels of extracellular ubiquitin (UB), and UB inhibits β‐AR‐stimulated cardiac myocyte apoptosis. We hypothesized that exogenous UB plays a protective role in chronic β‐AR‐stimulated myocyte apoptosis and myocardial remodeling. Mice were infused with vehicle (sham), UB (1μg/g/h), isoproterenol (ISO; 400μg/kg/h) or UB+ISO using mini‐osmotic pumps. Left ventricular (LV) structural and functional remodeling was studied 7 days after infusion. ISO‐infusion similarly increased heart weight:body weight ratio in both ISO groups. M‐mode echocardiography indicated increased percent fractional shortening and ejection fraction in ISO, not UB+ISO, group. Isovolumic contraction and relaxation times, as measured using Doppler echocardiography, were significantly lower in ISO vs UB+ISO. The increase in cardiac myocyte apoptosis and fibrosis was significantly greater in ISO vs UB+ISO. Akt activity was higher, while GSK‐3β activity was lower in UB+ISO vs ISO. MMP‐2 expression and activity was higher in UB+ISO, while increased MMP‐9 expression was only observed in UB+ISO hearts. In vitro, UB treatment enhanced MMP‐2 expression and activity and increased MMP‐9 expression in adult cardiac fibroblasts. Exogenous UB plays a crucial role in β‐AR‐stimulated myocardial remodeling with effects on LV function, fibrosis and myocyte apoptosis. Supported by HL‐091405, HL‐092459 and BX000640