Pacher Pal, Szabo Csaba
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.
Am J Pathol. 2008 Jul;173(1):2-13. doi: 10.2353/ajpath.2008.080019. Epub 2008 Jun 5.
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.
在过去的20年里，来自体外研究和疾病临床前模型的实验证据表明，在中风、心肌及其他形式的再灌注损伤、心肌肥大和心力衰竭、心肌病、循环性休克、心血管衰老、损伤后的动脉粥样硬化和血管重塑、糖尿病并发症以及神经退行性疾病过程中，实质细胞、内皮细胞和浸润性炎症细胞会产生活性氧和氮物质，包括活性氧化剂过氧亚硝酸根。过氧亚硝酸根和其他活性物质会诱导氧化性DNA损伤，进而激活核酶聚（ADP-核糖）聚合酶1（PARP-1），它是PARP酶家族中最丰富的亚型。PARP过度激活会耗尽其底物NAD(+)，减缓糖酵解、电子传递和ATP生成的速率，最终导致细胞功能受损或死亡，以及各种促炎途径的上调。在相关的疾病动物模型中，过氧亚硝酸根的中和或PARP的药理学抑制具有显著的治疗益处。因此，新型抗氧化剂和PARP抑制剂已进入临床开发阶段，用于各种心血管疾病和其他疾病的实验性治疗。本综述重点关注过氧亚硝酸根-PARP途径在多种不同疾病（从心肌缺血/再灌注损伤、心肌炎、心力衰竭、循环性休克和糖尿病并发症到动脉粥样硬化、关节炎、结肠炎和神经退行性疾病）中的病理生理相关性的现有人类数据。
