Activation of poly(ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging.
Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of 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 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 micromol/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.
Pacher
Pal
P
Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915, USA.
Mabley
Jon G
JG
Soriano
Francisco G
FG
Liaudet
Lucas
L
Szabó
Csaba
C
D000109:Acetylcholine / Q000494:pharmacology; D000322:Adrenergic Agonists / Q000494:pharmacology; D000375:Aging; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D004727:Endothelium / Q000473:pathology; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D006439:Hemodynamics; D006973:Hypertension; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology
D000322:Adrenergic Agonists; D001057:Apolipoproteins E; D014665:Vasodilator Agents; D011065:Poly(ADP-ribose) Polymerases; D000109:Acetylcholine; D004837:Epinephrine