TY - JOUR
T1 - Single dose treatment with PARP-inhibitor INO-1001 improves aging-associated cardiac and vascular dysfunction
AU - Radovits, Tamás
AU - Seres, Leila
AU - Gero, Domokos
AU - Berger, Irina
AU - Szabó, Csaba
AU - Karck, Matthias
AU - Szabó, Gábor
N1 - Funding Information:
This work was supported by a Grant from the German Research Foundation (SFB 414) to G.S. and by the Hungarian Research Fund (OTKA AT049488) and the National Institutes of Health (R01 GM060915) to C.S. The expert technical assistance of Anne Schuppe and Heike Ziebart are gratefully acknowledged.
PY - 2007/7
Y1 - 2007/7
N2 - 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.
AB - 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.
KW - Aging
KW - Cardiac function
KW - Endothelial function
KW - Immunohistochemistry
KW - Nitro-oxidative stress
KW - Poly(ADP-ribose) polymerase
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U2 - 10.1016/j.exger.2007.01.013
DO - 10.1016/j.exger.2007.01.013
M3 - Article
C2 - 17383839
AN - SCOPUS:34248584872
SN - 0531-5565
VL - 42
SP - 676
EP - 685
JO - Experimental Gerontology
JF - Experimental Gerontology
IS - 7
ER -