TY - JOUR
T1 - Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure
AU - Pacher, Pál
AU - Liaudet, Lucas
AU - Mabley, Jon G.
AU - Komjáti, Katalin
AU - Szabó, Csaba
N1 - Funding Information:
Dr. Pacher is on leave from the Institute of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary. This work was supported by a grant from the National Institutes of Health (R01 HL 59266) to Dr. Szabó.
PY - 2002/9/4
Y1 - 2002/9/4
N2 - OBJECTIVES. We investigated the effects of a novel ultrapotent poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, PJ34, on cardiac and endothelial dysfunction in a rat model of chronic heart failure (CHF). BACKGROUND. Overactivation of the nuclear enzyme PARP importantly contributes to the development of cell dysfunction and tissue injury in various pathophysiologic conditions associated with oxidative stress, including myocardial reperfusion injury, heart transplantation, stroke, shock, and diabetes. METHODS. Chronic heart failure was induced in Wistar rats by chronic ligation of the left anterior descending coronary artery. Left ventricular (LV) function and ex vivo vascular contractility and relaxation were measured 10 weeks after the surgery. Nitrotyrosine (NT) formation and PARP activation were detected by immunohistochemistry. RESULTS. Chronic heart failure induced increased NT formation and PARP activation in the myocardium and intramural vasculature, depressed LV performance, and impaired vascular relaxation of aortic rings. PJ34 significantly decreased myocardial PARP activation but not NT formation, and improved both cardiac dysfunction and vascular relaxation. CONCLUSIONS. Poly(ADP-ribose) polymerase inhibition represents a novel approach for the experimental treatment of CHF.
AB - OBJECTIVES. We investigated the effects of a novel ultrapotent poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, PJ34, on cardiac and endothelial dysfunction in a rat model of chronic heart failure (CHF). BACKGROUND. Overactivation of the nuclear enzyme PARP importantly contributes to the development of cell dysfunction and tissue injury in various pathophysiologic conditions associated with oxidative stress, including myocardial reperfusion injury, heart transplantation, stroke, shock, and diabetes. METHODS. Chronic heart failure was induced in Wistar rats by chronic ligation of the left anterior descending coronary artery. Left ventricular (LV) function and ex vivo vascular contractility and relaxation were measured 10 weeks after the surgery. Nitrotyrosine (NT) formation and PARP activation were detected by immunohistochemistry. RESULTS. Chronic heart failure induced increased NT formation and PARP activation in the myocardium and intramural vasculature, depressed LV performance, and impaired vascular relaxation of aortic rings. PJ34 significantly decreased myocardial PARP activation but not NT formation, and improved both cardiac dysfunction and vascular relaxation. CONCLUSIONS. Poly(ADP-ribose) polymerase inhibition represents a novel approach for the experimental treatment of CHF.
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U2 - 10.1016/S0735-1097(02)02062-4
DO - 10.1016/S0735-1097(02)02062-4
M3 - Article
C2 - 12225730
AN - SCOPUS:0037019589
SN - 0735-1097
VL - 40
SP - 1006
EP - 1016
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 5
ER -