Selegiline attenuates cardiac oxidative stress and apoptosis in heart failure: association with improvement of cardiac function

Abstract

We have shown recently that selegiline exerts a cardiac neuroprotective effect in chronic heart failure. Since selegiline has an antioxidant antiapoptotic effect, we proposed to determine whether selegiline attenuates cardiac oxidative stress and myocyte apoptosis in chronic heart failure by modulating Bcl-2 and Bax protein expression, and whether the effects are associated with the improvement of cardiac function. Rabbits with rapid cardiac pacing (360 beats/min) and sham operation without pacing were randomized to receive oral selegiline (1 mg/day) or placebo for 8 weeks. Echocardiography was used to measure left ventricular fractional shortening. After 8 weeks of treatment, animals were studied for arterial norepinephrine and left ventricular systolic function (fractional shortening and dP/dt), and were then sacrificed for measuring the stable oxidative product of myocardial mitochondrial DNA (mtDNA) 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), myocyte apoptosis by monoclonal antibody to single stranded DNA, and Bcl-2 and Bax protein expression by Western blot and immunohistochemistry. Rapid cardiac pacing increased plasma norepinephrine, cardiac oxidative stress and myocyte apoptosis, reduced Bcl-2 and the Bcl-2 to Bax ratio. These changes were associated with decreased left ventricular fractional shortening and dP/dt. Selegiline treatment in chronic heart failure animals reduced plasma norepinephrine, cardiac oxidative stress and myocyte apoptosis, prevented the changes of Bcl-2 and Bcl-2 to Bax ratio, and improved left ventricular fractional shortening and dP/dt. The findings suggest that the reduction by selegiline of myocyte apoptosis is related to the decrease of cardiac oxidative stress and the modulation of apoptotic and antiapoptotic proteins. The antioxidant antiapoptotic effects of selegiline are potentially beneficial in the improvement of cardiac function in chronic heart failure.