Abstract. Increased production of reactive oxygen and nitrogen species has recently been implicated in the patho- genesis of endothelial dysfunction associated with athero- sclerosis, 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 and circulatory shock. Here we investigated the role of PARP activation in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension and aging. Retired breeder spontaneously hypertensive rats (SHR, 40 weeks old) and apolipoprotein E knockout mice (apoE-Ko, 10 weeks old) were treated for 20 weeks with vehicle or the potent PARP inhibitor PJ34. In the vehicle-treated SHR rats and apoE-Ko mice (kept on atherogenic diet) there was a significant loss of endothelial function, as measured by the relaxant responsiveness of vascular rings to acetylcholine. SHR rats also developed severe hypertension and cardiac hypertrophy. Treatment with the PARP inhibitor did not influence high blood pressure and cardiac hypertrophy in SHR rats, but it improved Ach-induced, NO-mediated vascular relaxation. In addition to the beneficial effects of chronic treatment with PARP inhibitor, 1-h in vitro incubation of aortic rings from SHR rats with PJ34 (3 µmol/l) was also able to improve the endothelial dysfunction. In contrast, in apoE-Ko mice PJ34 treatment did not affect the parameters studied. Thus, PARP activation contributes to the pathogenesis of endothelial dysfunction associated with hypertension and aging, but not in the current experimental model of atherosclerosis. Introduction Impaired endothelial function has been widely described both in animal models and in humans in atherosclerosis, hyper- tension and aging. There is circumstantial evidence that the endothelial dysfunction associated with these conditions is, at least in part, related to the local formation of reactive oxygen and nitrogen species within and in the vicinity of the vascular endothelium (1-18). Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP) leading to endothelial dysfunction in various patho- physiological conditions including reperfusion, shock, diabetes (19-26). Here we investigated whether the loss of endothelial function associated with hypertension and aging in rats and atherosclerosis in mice is dependent upon the PARP pathway within the vasculature. Materials and methods The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by US National Institutes of Health (NIH Publication No. 85-23 revised 1985) and was performed with the approval of the local Institutional Animal Care and Use Committee. Animals, treatment protocols. Retired ex-breeder male spontaneous hypertensive rats (SHR, 40 weeks old) were treated with vehicle (n=15) or the PARP inhibitor PJ34 (n=15; 20 mg/kg/day PO) for 20 weeks. This dose regimen was found to effectively inhibit vascular PARP activation in previous studies (24-26). Eight weeks old male Wistar-Kyoto (WKY) rats treated with vehicle (n=15) or PJ34 (n=15; 20 mg/kg/day PO) for 20 weeks were used as controls. Apolipoprotein E knockout mice (apoE-Ko, 10 weeks old) and age-matched controls were kept on atherogenic diet (ICN Biomedicals Inc., Aurora, OH) and were treated for 20 weeks with vehicle or the PARP inhibitor PJ34. Measurement of vascular reactivity in isolated aortic rings of rats and mice. The method has been described previously (24- 26). Briefly, the thoracic aorta was cleared from periadventitial fat and cut into 1-2 mm (in mice) or 3-4 mm (in rats) width INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 9: 659-664, 2002 659 Activation of poly(ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging PAL PACHER 1 , JON G. MABLEY 1 , FRANCISCO G. SORIANO 2 , LUCAS LIAUDET 2 and CSABA SZABÓ 1,2 1 Inotek Corporation, Suite 419E,100 Cummings Center, Beverly, MA 01915; 2 Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry New Jersey, 185 University Heights, Newark, NJ 01703, USA Received February 27, 2002; Accepted April 3, 2002 _________________________________________ Correspondence to: Dr Csaba Szabó, Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915, USA E-mail: szabocsaba@aol.com Abbreviations: PARP, poly(ADP-ribose) polymerase; BP, blood pressure; LVEDP, left ventricular end-diastolic pressure; LVSP, left ventricular systolic pressure; +dP/dt, maximal slope of systolic pressure increment; -dP/dt, maximal slope of diastolic pressure decrement; SHR, spontaneous hypertensive rats Key words: hypertension, aging, atherosclerosis, vasorelaxation, acetylcholine, oxidative stress, blood pressure