Journal
EXPERIMENTAL GERONTOLOGY
Volume 42, Issue 7, Pages 676-685Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2007.01.013
Keywords
aging; nitro-oxidative stress; poly(ADP-ribose) polymerase; cardiac function; endothelial function; immunohistochemistry
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Funding
- NIGMS NIH HHS [R01 GM060915, R01 GM060915-01] Funding Source: Medline
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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. (C) 2007 Elsevier Inc. All rights reserved.
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