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

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

Research output: Contribution to journalArticle

32 Citations (Scopus)

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
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Blood Vessels
Aging of materials
Endothelium
Oxidative Stress
Oxidative stress
Poly Adenosine Diphosphate Ribose
Therapeutics
Nitroprusside
Ventricular Pressure
Cardiovascular System
Animals
Oxidants
Vasodilation
Chemical activation
DNA Damage
Acetylcholine
Tissue
Reactive Oxygen Species
Cardiovascular system

Keywords

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

ASJC Scopus subject areas

  • Aging
  • Medicine(all)

Cite this

Single dose treatment with PARP-inhibitor INO-1001 improves aging-associated cardiac and vascular dysfunction. / Radovits, Tamás; Seres, Leila; Gero, Domokos; Berger, Irina; Szabo, Csaba; Karck, Matthias; Szabó, Gábor.

In: Experimental Gerontology, Vol. 42, No. 7, 07.2007, p. 676-685.

Research output: Contribution to journalArticle

Radovits, Tamás ; Seres, Leila ; Gero, Domokos ; Berger, Irina ; Szabo, Csaba ; Karck, Matthias ; Szabó, Gábor. / Single dose treatment with PARP-inhibitor INO-1001 improves aging-associated cardiac and vascular dysfunction. In: Experimental Gerontology. 2007 ; Vol. 42, No. 7. pp. 676-685.
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