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

Tamás Radovits, Leila Seres, Domokos Gero, Irina Berger, Csaba Szabó, Matthias Karck, Gábor Szabó

    Research output: Contribution to journalArticle

    34 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)676-685
    Number of pages10
    JournalExperimental Gerontology
    Volume42
    Issue number7
    DOIs
    StatePublished - Jul 2007

    Keywords

    • Aging
    • Cardiac function
    • Endothelial function
    • Immunohistochemistry
    • Nitro-oxidative stress
    • Poly(ADP-ribose) polymerase

    ASJC Scopus subject areas

    • Biochemistry
    • Aging
    • Molecular Biology
    • Genetics
    • Endocrinology
    • Cell Biology

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