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

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.

Figure 1

The nitric oxide-peroxynitrite-PARP pathway in health and disease. Nitric oxide (NO) activates the soluble guanylate cyclase (sGC)-cyclic guanosine-3′,5′-monophosphate (cGMP) signal transduction pathway and mediates various physiological/beneficial effects including synaptic plasticity; vasodilation; inhibition of platelet aggregation; anti-inflammatory, anti-remodeling, and anti-apoptotic effects; just mentioning a few. Under pathophysiological conditions (eg, stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders, and so forth), nitric oxide and superoxide (·O₂⁻) react to form peroxynitrite (ONOO⁻) that induces cell damage via lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration, and also activation of stress signaling, matrix metalloproteinases (MMPs) among others. Mitochondrial enzymes are particularly vulnerable to attacks by peroxynitrite, leading to reduced ATP formation and induction of mitochondrial permeability transition by opening of the permeability transition pore (PTP), which dissipates the mitochondrial membrane potential (ΔΨ). These events result in cessation of electron transport and ATP formation, mitochondrial swelling, and permeabilization of the outer mitochondrial membrane, allowing the efflux of several proapoptotic molecules, including cytochrome c and apoptosis-inducing factor (AIF). In turn, cytochrome c and AIF activate a series of downstream effectors that mediate caspase-dependent and -independent apoptotic death pathways. In addition to its damaging effects on mitochondria, peroxynitrite, in concert with other oxidants, causes oxidative injury to DNA, resulting in DNA strand breakage which in turn activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP-1). Activated PARP-1 consumes NAD to build up poly(ADP-ribose) polymers (PAR), which are themselves rapidly metabolized by the activity of poly(ADP-ribose) glycohydrolase (PARG). Some free PAR may exit the nucleus and travel to the mitochondria, where they amplify the mitochondrial efflux of AIF (nuclear to mitochondria cross talk). Depending on the severity of the initial damage by peroxynitrite and other oxidants, the injured cell may either recover or die. In the latter case, the cell may be executed by apoptosis in case of moderate mitochondrial PTP opening and PARP-1 activation with preservation of cellular ATP, or by necrosis in case of widespread PTP opening and PARP-1 overactivation, leading to massive NAD consumption and collapse of cellular ATP. Overactivated PARP-1 also facilitates the expression of a variety of inflammatory genes leading to increased inflammation and associated tissue injury.

Figure 2

Exogenous/endogenous, regulators/modulators of PARP activity. Various endogenous factors can influence PARP activity either by forming a complex with PARP or inhibiting the binding of its substrate NAD⁺ to the active site of the enzyme. Such examples may include estrogen (E), thyroid hormones (T), nicotinamide (NA), NAD⁺ metabolites, and vitamin D. PARP activity can also be modulated by various kinases by phosphorylation (eg, MAP kinases and PKC), and PARP can modulate kinase (eg, AKT) activity. Different exogenous factors (eg, caffeine and its endogenously formed metabolites, theophylline, and tetracycline antibiotics) may also modulate PARP activity.