FIG. 9.
Role of nitric oxide (NO) and peroxynitrite in cardiovascular pathophysiology. On the one hand, NO by activating soluble guanylate cyclase (sGC)-cGMP signal transduction pathway mediates various physiological/beneficial effects in the cardiovascular system including vasodilation, inhibition of platelet aggregation, anti-inflammatory, antiremodelling, and antiapoptotic effects. On the other hand, under pathological conditions associated with increased oxidative stress and inflammation (myocardial infarction, ischemic heart disease, myocarditis, cardiomyopathy, hypertension, etc.), NO and superoxide (O2•−) react to form peroxynitrite (ONOO−) which 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 (see also Table 2). Peroxynitrite also triggers the release of proapoptotic factors such as cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria, which mediate caspase-dependent and -independent apoptotic death pathways. Moreover, peroxynitrite, in concert with other oxidants, causes stand breaks in DNA, activating the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). Mild damage of DNA activates the DNA repair machinery. In contrast, once excessive oxidative and nitrosative stress-induced DNA damage occurs, like in various forms of myocardial reperfusion injury and heart failure, overactivated PARP initiates an energy-consuming cycle by transferring ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to nuclear proteins, resulting in rapid depletion of the intracellular NAD+ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death. Poly(ADP-ribose) glycohydrolase (PARG) degrades poly(ADP-ribose) (PAR) polymers, generating free PAR polymer and ADP-ribose. Overactivated PARP also facilitates the expression of a variety of inflammatory genes leading to increased inflammation and associated oxidative stress, thus facilitating the progression of cardiovascular dysfunction and heart failure.