Overactivation of the nuclear
enzyme poly(ADP-ribose) polymerase (PARP) contributes to the development of cell dysfunction and tissue injury in various pathophysiological conditions associated with oxidative and nitrosative stress, including
myocardial reperfusion injury,
heart transplantation,
diabetic cardiomyopathy and chronic
heart failure. In recent studies, we have demonstrated the beneficial effects of a novel ultrapotent
PARP inhibitor,
INO-1001, on cardiac and endothelial dysfunction and remodeling in rat model of advanced aging-associated chronic
heart failure and in a mouse model of
heart failure induced by aortic banding. In the current study, we have investigated the effect of
INO-1001 on the development of
heart failure induced by permanent
ligation of the left anterior descending coronary artery,
heart failure induced by
doxorubicin and acute myocardial dysfunction induced by bacterial
endotoxin. In the coronary
ligation model, a significantly depressed left ventricular performance and impaired vascular relaxation of aortic rings were found, and PARP inhibition significantly improved both cardiac function and vascular relaxation. In the
doxorubicin model, a single injection of
doxorubicin induced high mortality and a significant decrease in left ventricular systolic pressure, +dP/dt, -dP/dt, stroke volume,
stroke work, ejection fraction and cardiac output. Treatment with the
PARP inhibitor reduced
doxorubicin-induced mortality and markedly improved cardiac function. PARP inhibition did not interfere with
doxorubicin's antitumor effect. In the
endotoxin model of cardiac dysfunction, PARP inhibition attenuated the suppression of myocardial contractility elicited by
endotoxin. The current data strengthen the view that PARP inhibition may represent an effective approach for the
experimental therapy of various forms of acute and chronic
heart failure.