Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. 2008

Pal Pacher, and Csaba Szabo
Section on Oxidative Stress and Tissue Injury, Laboratory of Physiologic Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413, USA. pacher@mail.nih.gov

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.

UI MeSH Term Description Entries
D011065 Poly(ADP-ribose) Polymerases Enzymes that catalyze the transfer of multiple ADP-RIBOSE groups from nicotinamide-adenine dinucleotide (NAD) onto protein targets, thus building up a linear or branched homopolymer of repeating ADP-ribose units i.e., POLY ADENOSINE DIPHOSPHATE RIBOSE. ADP-Ribosyltransferase (Polymerizing),Poly ADP Ribose Polymerase,Poly(ADP-Ribose) Synthase,Poly(ADP-ribose) Polymerase,PARP Polymerase,Poly ADP Ribose Transferase,Poly ADP-Ribose Synthase,Poly(ADP-Ribose) Transferase,Poly(ADPR) Polymerase,Poly(ADPribose) Polymerase,Poly ADP Ribose Synthase,Polymerase, PARP,Synthase, Poly ADP-Ribose
D002986 Clinical Trials as Topic Works about pre-planned studies of the safety, efficacy, or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. This concept includes clinical trials conducted both in the U.S. and in other countries. Clinical Trial as Topic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D016877 Oxidants Electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (OXIDATION-REDUCTION). Oxidant,Oxidizing Agent,Oxidizing Agents,Agent, Oxidizing,Agents, Oxidizing
D018384 Oxidative Stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). Anti-oxidative Stress,Antioxidative Stress,DNA Oxidative Damage,Nitro-Oxidative Stress,Oxidative Cleavage,Oxidative DNA Damage,Oxidative Damage,Oxidative Injury,Oxidative Nitrative Stress,Oxidative Stress Injury,Oxidative and Nitrosative Stress,Stress, Oxidative,Anti oxidative Stress,Anti-oxidative Stresses,Antioxidative Stresses,Cleavage, Oxidative,DNA Damage, Oxidative,DNA Oxidative Damages,Damage, DNA Oxidative,Damage, Oxidative,Damage, Oxidative DNA,Injury, Oxidative,Injury, Oxidative Stress,Nitrative Stress, Oxidative,Nitro Oxidative Stress,Nitro-Oxidative Stresses,Oxidative Cleavages,Oxidative DNA Damages,Oxidative Damage, DNA,Oxidative Damages,Oxidative Injuries,Oxidative Nitrative Stresses,Oxidative Stress Injuries,Oxidative Stresses,Stress Injury, Oxidative,Stress, Anti-oxidative,Stress, Antioxidative,Stress, Nitro-Oxidative,Stress, Oxidative Nitrative,Stresses, Nitro-Oxidative
D030421 Peroxynitrous Acid A potent oxidant synthesized by the cell during its normal metabolism. Peroxynitrite is formed from the reaction of two free radicals, NITRIC OXIDE and the superoxide anion (SUPEROXIDES). Peroxynitrite,Peroxonitrite,Peroxynitrous Acid, Potassium Salt,Acid, Peroxynitrous,Acids, Peroxynitrous,Peroxonitrites,Peroxynitrites,Peroxynitrous Acids

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