Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease

Pal Pacher, Csaba Szabo

Research output: Contribution to journalArticle

247 Citations (Scopus)

Abstract

Throughout the last 2 decades, experimental evidence from in vitro studies and preclinical models of disease has demonstrated that reactive oxygen and nitrogen species, including the reactive oxidant peroxynitrite, are generated in parenchymal, endothelial , and infiltrating inflammatory cells during stroke, myocardial and other forms of reperfusion injury, myocardial hypertrophy and heart failure, cardiomyopathies, circulatory shock, cardiovascular aging, atherosclerosis and vascular remodeling after injury, diabetic complications, and neurodegenerative disorders. Peroxynitrite and other reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), the most abundant isoform of the PARP enzyme family. PARP overactivation depletes its substrate NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to functional impairment or death of cells, as well as up-regulation of various proinflammatory pathways. In related animal models of disease, peroxynitrite neutralization or pharmacological inhibition of PARP provides significant therapeutic benefits. Therefore, novel antioxidants and PARP inhibitors have entered clinical development for the experimental therapy of various cardiovascular and other diseases. This review focuses on the human data available on the pathophysiological relevance of the peroxynitrite-PARP pathway in a wide range of disparate diseases, ranging from myocardial ischemia/reperfusion injury, myocarditis, heart failure, circulatory shock, and diabetic complications to atherosclerosis, arthritis, colitis, and neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)2-13
Number of pages12
JournalAmerican Journal of Pathology
Volume173
Issue number1
DOIs
StatePublished - Jul 2008
Externally publishedYes

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Peroxynitrous Acid
Poly(ADP-ribose) Polymerases
Heart Failure
Diabetes Complications
Reperfusion Injury
Neurodegenerative Diseases
Shock
Atherosclerosis
Myocardial Reperfusion Injury
Animal Disease Models
Reactive Nitrogen Species
Investigational Therapies
Enzyme Activation
Myocarditis
Glycolysis
Colitis
Electron Transport
Cardiomyopathies
Oxidants
NAD

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. / Pacher, Pal; Szabo, Csaba.

In: American Journal of Pathology, Vol. 173, No. 1, 07.2008, p. 2-13.

Research output: Contribution to journalArticle

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