ABSTRACT
Poly(adenosine 5′-diphosphate ribose) polymerase (PARP), also known as poly(ADP-ribose) synthetase (PARS; EC 2.4.2.30), is a chromatin-bound enzyme, which is abundantly present in the nuclei of numerous cell types. Single-strand breaks in DNA trigger the activation of PARP, which transfers ADP-ribose moieties from NAD+ to various nuclear proteins including histones and PARP (automodification domain) itself. This reaction leads to the generation of nicotinamide, which is an inhibitor (negative feedback) of PARP activity. Continuous or excessive activation of PARP produces extended chains of ADP-ribose on nuclear proteins and results in a substantial depletion of intracellular NAD+. As NADH functions as an electron carrier in the mitochondrial respiratory chain, NAD+ depletion rapidly leads to a fall in intracellular ATP levels. Moreover, nicotinamide can be recycled to NAD+
in a reaction that consumes ATP. Thus, excessive activation of PARP leads to a fall in ATP (by two different mechanisms), which may ultimately cause cell death.1,2 Oxygen-derived radicals including superoxide anions, hydrogen peroxide, or hydroxyl radicals cause strand breaks in DNA, activation of PARP and depletion of NAD+ and ATP in cultured cells. Peroxynitrite, which is generated when equimolar amounts of nitric oxide (NO) react with superoxide anions, also causes strand breaks in DNA, activation of PARP, and ultimately cell death.3 In 1997, we discovered that various, chemically distinct inhibitors of PARP reduce the degree of tissue injury caused by ischemia-reperfusion of the heart and skeletal muscle.4 This chapter reviews the role of PARP in the pathophysiology of ischemia-reperfusion injury of the heart and focuses on the cardioprotective effects of inhibitors of PARP activity in conditions associated with myocardial ischemia and reperfusion.
