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Myocardial Postischemic Injury Is Reduced by PolyADPribose Polymerase-1 Gene Disruption

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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.

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Acknowledgments

We thank David K. Krug, Dan Guastella, Penghai Wang, and Dr. S. Sankarapandi for technical assistance, and Jan Fertmann for assistance in data preparation. We thank Dr. Jie Zhang, Dr. Ted Dawson, and Dr. Valina Dawson for advice. We thank NEN Life Science Products for synthesis and donation of [33P] NAD+. We thank Dr. Z. Q. Wang for generously providing PARP-1−/− breeding pairs used to create the colony of mice for this study. This research was supported by NIH grants HL-38324, HL-63744, an American Heart Association Grant in Aid (JLZ), MH-18501, DA-00266, Research Scientist Award DA-00074 (SHS), and NIMH training grant M418 (AAP). One of the authors (SHS) is a consultant, director and member of the scientific advisory board of Guilford Pharmaceuticals, Inc. which is developing drugs based on PARP technology.

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Authors and Affiliations

  1. Departments of Neuroscience, Pharmacology & Molecular Science, and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Andrew A. Pieper &  Solomon H. Snyder

  2. Molecular and Cellular Biophysics Laboratories, Department of Medicine, Division of Cardiology and the Electron Paramagnetic Resonance Center, The Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA

    Thorsten Walles, Guo Wei &  Jay L. Zweier

  3. Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

    Emily E. Clements & Ajay Verma

  4. Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, LA.14, Baltimore, MD, 21224, USA

    Solomon H. Snyder

  5. Johns Hopkins University, School of Medicine, 725 N. Wolfe St., Baltimore, MD, 21205, USA

    Jay L. Zweier

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  1. Andrew A. Pieper
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Corresponding author

Correspondence to Solomon H. Snyder.

Additional information

Communicated by S. Snyder.

Contributed equally to this work.

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Pieper, A.A., Walles, T., Wei, G. et al. Myocardial Postischemic Injury Is Reduced by PolyADPribose Polymerase-1 Gene Disruption. Mol Med 6, 271–282 (2000). https://doi.org/10.1007/BF03401936

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