Mechanism of PARP activation and its role in cellular energy depletion and injury.
Ischemia causes intracellular ATP depletion that activates pathways of oxygen radical generation, including that from xanthine oxidase. Peroxynitrite and hydroxyl radicals elicit polyADP-ribosylation through damaging DNA. Excessive polyADPribosylation depletes intracellular NAD+, which can only be replaced at the expense of intracellular ATP pools. This further depletes cellular ATP. As this cycle continues, oxidant injury and ATP depletion result in accumulated cellular injury and death. NO, nitric oxide; NOS, nitric oxide synthase; PARP, polyADPribose polymerase.