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CARDIOVASCULAR

A New, Potent Poly(ADP-ribose) Polymerase Inhibitor Improves Cardiac and Vascular Dysfunction Associated with Advanced Aging

Pál Pacher, Anne Vaslin, Rita Benk, Jon G. Mabley, Lucas Liaudet, György Haskó, Anita Marton, Sándor Bátkai, Márk Kollai, and Csaba Szabó

Inotek Pharmaceuticals Corporation, Beverly, Massachusetts (P.P., A.V., R.B., J.G.M., A.M., C.S.); Laboratory of Physiologic Studies, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Bethesda, Maryland (P.P., S.B.); Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (G.H.); Department of Pharmacology and Pharmacotherapy (P.P.) and Institute of Human Physiology and Clinical Experimental Research (R.B., M.K., C.S.), Semmelweis University, Budapest, Hungary; Critical Care Division, Department of Internal Medicine, University Hospital, Lausanne, Switzerland (L.L.); and Department of Surgery, University of Medicine and Dentistry, New Jersey Medical School, Newark, New Jersey (G.H., C.S.)

Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension, and aging. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury, circulatory shock, and aging. Here, we investigated the effect of a new PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction associated with advanced aging using Millar's new Aria pressure-volume conductance system and isolated aortic rings. Young adult (3 months old) and aging (24 months old) Fischer rats were treated for 2 months with vehicle, or the potent PARP inhibitor INO-1001. In the vehicle-treated aging animals, there was a marked reduction of both systolic and diastolic cardiac function and loss of endothelial relaxant responsiveness of aortic rings to acetylcholine. Treatment with INO-1001 improved cardiac performance in aging animals and also acetylcholine-induced, nitric oxide-mediated vascular relaxation. Thus, pharmacological inhibition of PARP may represent a novel approach to improve cardiac and vascular dysfunction associated with aging.

Address correspondence to: Dr. Pál Pacher, National Institutes of Health, National Institute on Alcohol Abuse & Alcoholism, Park Bldg., Rm. 445, 12420 Parklawn Drive, MSC-8115, Bethesda, MD 20892-8115. E-mail: pacher{at}mail.nih.gov

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