Single dose treatment with PARP-inhibitor INO-1001 improves aging-associated cardiac and vascular dysfunction

Abstract

Overproduction of reactive oxygen species in aging tissues has been implicated in the pathogenesis of aging-associated cardiovascular dysfunction. Oxidant-induced DNA-damage activates the poly(ADP-ribose) polymerase (PARP) pathway, leading to tissue injury. In this study we investigated the acute effects of the PARP inhibitor INO-1001 on aging-associated cardiac and endothelial dysfunction. Using a pressure-volume conductance catheter, left ventricular pressure-volume analysis of young and aging rats was performed before and after a single injection of INO-1001. Endothelium-dependent and -independent vasorelaxation of isolated aortic rings were investigated by using acetylcholine and sodium nitroprusside. Aging animals showed a marked reduction of myocardial contractility and endothelium-dependent relaxant responsiveness of aortic rings. Single dose INO-1001-treatment resulted in acute improvement in their cardiac and endothelial function. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) confirmed enhanced nitro-oxidative stress and PARP-activation in aging animals. Acute treatment with INO-1001 decreased PARP-activation, but did not affect nitrotyrosine-immunoreactivity. Our results demonstrate that the aging-associated chronic cardiovascular dysfunction can be improved, at least, short term, by a single treatment course with a PARP-inhibitor, supporting the role of the nitro-oxidative stress -- PARP -- pathway in the age-related functional decline of the cardiovascular system. Pharmacological inhibition of PARP may represent a novel therapeutic utility to improve aging-associated cardiovascular dysfunction.

Improvement of Aging-Associated Cardiovascular Dysfunction by the Orally Administered Copper(II)-Aspirinate Complex

“…The endothelium-independent relaxation induced by the exogenously administered NO donor SNP was not impaired by aging, indicating the normal dilative capacity of the vascular smooth muscle. In contrast with a previous work using epinephrine for precontraction, 37 we found a significant decrease in contraction forces induced by PE in aging animals that was in line with our previous studies 7,21 and may be due to alterations in receptor density and/or receptor/effector coupling. Similar to the effects of aspirin, 23 the SODmimetic tempol, 19 or catalytic peroxynitrite decomposition, 7 CuAsp treatment significantly enhanced the endotheliumdependent vasorelaxations (i.e., improved the endothelial function) in rats with advanced aging, whereas endotheliumindependent vasorelaxation was only slightly increased.…”

“…1 and 2 fects of the PARP inhibitors or peroxynitrite decomposition catalysts in age-related cardiac dysfunction. 7,20,21 We found that CuAsp did not affect cardiovascular functions of young rats. Thus, the improved cardiovascular function seen in the aging treatment group is a specific phenomenon, reflecting a reversal of aging-associated suppressed cardiovascular performance rather than the consequence of nonspecific direct cardiac/vascular effects of CuAsp.…”

“…With respect to human cardiovascular aging, the major limitation of our rodent model is that MAP, as reported also by other recent studies, 7,20,21,28 …”

“…On the basis of results of recent cardiovascular studies, pharmacological treatment with synthetic superoxide dismutase (SOD) mimetics, 19 peroxynitrite decomposition catalysts, 7 or PARP inhibitors 20,21 emerge as novel antioxidant therapeutic possibilities for aging-associated cardiovascular dysfunction. Most recently, chronic aspirin supplementation has been shown to reduce aging-associated "molecular inflammation" and NiOxStr and improve vascular dysfunction at old age.…”

Pharmacological Interventions to Prevent Vascular Endothelial Dysfunction: Future Directions

“…142) PARP inhibitors such as PJ-34 and INO 1001 exert beneficial effects against diabetes, hyperhomocysteinemia, hypertension, aging and en-dotoxic shock-induced VED. 141,[143][144][145][146] Activation of Akt stimulates phosphorylation of eNOS, increases the production of NO and reduces oxidative stress. [147][148][149] Demethylasterriquinone B1 (DAQ B1), an activator of Akt has reduced oxidative stress and prevented hypertension, diabetes mellitus and hyperhomocyteinemia associated VED.…”