A new, potent poly(ADP-ribose) polymerase inhibitor improves cardiac and vascular dysfunction associated with advanced aging.
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.
Pacher
Pál
P
National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Park Bldg. Rm. 445, 12420 Parklawn Drive, MSC-8115, Bethesda, MD 20892-8115, USA. pacher@mail.nih.gov
Vaslin
Anne
A
Benko
Rita
R
Mabley
Jon G
JG
Liaudet
Lucas
L
Haskó
György
G
Marton
Anita
A
Bátkai
Sándor
S
Kollai
Márk
M
Szabó
Csaba
C
D000375:Aging / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006331:Heart Diseases / Q000517:prevention & control; D006334:Heart Function Tests / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D014652:Vascular Diseases / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000187:drug effects*
D004791:Enzyme Inhibitors; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors