EXPERIMENTAL STUDY
Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure
P.ál Pacher, MD, PhD*,
Lucas Liaudet, MD  ,
Jon G. Mabley, PhD*,
Katalin Komjáti, MD, PhD*, and
Csaba Szabó, MD, PhD*,*
* Inotek Pharmaceuticals Corporation, Beverly, Massachusetts, USA
Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey, USA
Institute of Human Physiology and Experimental Research, Semmelweis University, Budapest, Hungary
Critical Care Division, Department of Internal Medicine, University Hospital, Lausanne, Switzerland
Manuscript received February 7, 2002;
revised manuscript received May 15, 2002,
accepted May 23, 2002.
* Reprint requests and correspondence: Dr. Csaba Szabó, Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, Massachusetts 01915, USA.
szabocsaba{at}aol.com
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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Abbreviations and Acronyms
| | CHF | | chronic heart failure | | DNA | | deoxyribonucleic acid | | +dP/dt | | systolic pressure increment | | –dP/dt | | diastolic pressure decrement | | iNOS | | inducible isoform of nitric oxide synthase | | LAD | | left anterior descending coronary artery | | LV | | left ventricle/ventricular | | LVSP | | left ventricular systolic pressure | | LVEDP | | left ventricular end-diastolic pressure | | NAD+ | | nicotinamide adenine dinucleotide | | 3-NT | | 3-nitrotyrosine | | PARP | | poly(adenosine diphosphate-ribose) polymerase | | PBS | | phosphate buffered saline | | SNK | | Student-Newman-Keuls |
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