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
Published Version
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