Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption.

A. A. Pieper, T. Walles, G. Wei, E. E. Clements, A. Verma, Solomon H Snyder, J. L. Zweier

Research output: Contribution to journalArticle

Abstract

BACKGROUND: PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD+ and ATP. MATERIALS AND METHODS: In vivo PARP activation in heart tissue slices was assayed through conversion of [33P]NAD+ into polyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD+ and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1(-/-)) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats treated with PARP inhibitors. RESULTS: Ischemia-reperfusion (I/R) augmented formation of nitric oxide, oxygen free radicals and PARP activity. I/R induced decreases in cardiac contractility and NAD+ levels were attenuated in PARP-1(-/-) mouse hearts. PARP inhibitors reduced myocardial infarct size in rats. Residual polyADPribosylation in PARP-1(-/-) hearts may reflect alternative forms of PARP. CONCLUSIONS: PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ischemia. PARP inhibitors may have therapeutic utility in myocardial disease.

Original languageEnglish (US)
Pages (from-to)271-282
Number of pages12
JournalMolecular Medicine
Volume6
Issue number4
StatePublished - Apr 2000

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NAD
Reperfusion
Ischemia
Wounds and Injuries
Genes
Reactive Oxygen Species
Nitric Oxide
Adenosine Triphosphate
Myocardial Infarction
Adenosine Diphosphate Ribose
DNA Breaks
Coronary Occlusion
Nuclear Proteins
Cardiomyopathies
Free Radicals
Myocardial Ischemia
Coronary Vessels
Cell Death
Staining and Labeling
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Pieper, A. A., Walles, T., Wei, G., Clements, E. E., Verma, A., Snyder, S. H., & Zweier, J. L. (2000). Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption. Molecular Medicine, 6(4), 271-282.

Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption. / Pieper, A. A.; Walles, T.; Wei, G.; Clements, E. E.; Verma, A.; Snyder, Solomon H; Zweier, J. L.

In: Molecular Medicine, Vol. 6, No. 4, 04.2000, p. 271-282.

Research output: Contribution to journalArticle

Pieper, AA, Walles, T, Wei, G, Clements, EE, Verma, A, Snyder, SH & Zweier, JL 2000, 'Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption.', Molecular Medicine, vol. 6, no. 4, pp. 271-282.
Pieper AA, Walles T, Wei G, Clements EE, Verma A, Snyder SH et al. Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption. Molecular Medicine. 2000 Apr;6(4):271-282.
Pieper, A. A. ; Walles, T. ; Wei, G. ; Clements, E. E. ; Verma, A. ; Snyder, Solomon H ; Zweier, J. L. / Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption. In: Molecular Medicine. 2000 ; Vol. 6, No. 4. pp. 271-282.
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