title: A new, potent poly(ADP-ribose) polymerase inhibitor improves cardiac and vascular dysfunction associated with advanced aging.
abstract: 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.
authors.affiliation: 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
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Anne
authors.initials: A
authors.lastname: Vaslin
authors.forename: Rita
authors.initials: R
authors.lastname: Benko
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Anita
authors.initials: A
authors.lastname: Marton
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Márk
authors.initials: M
authors.lastname: Kollai
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: 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*
chemical_list: D004791:Enzyme Inhibitors; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors