NADPH oxidase (Nox)
The NADPH oxidase (Nox) family is composed of seven Nox isoforms and the main catalytic function of Nox is the generation of superoxide from NADPH. Control of blood flow is mediated by NO produced mainly by endothelial nitric oxide synthase (eNOS). In order to reduce the vasodilating effects of NO, to effectively constrict blood flow from its ‘normal’ open state, the NO signal must be attenuated. This is achieved by Nox-derived superoxide released into the inter-cellular space where it reacts rapidly with NO to form peroxynitrite, converting the NO signal to one of vasoconstriction. Nox assembly is acutely regulated by Ang II while both Ang II and aldosterone affect Nox gene expression. (7) ATR blockers (ARB) suppress Ang II-stimulated production of superoxide by Nox, thereby increasing NO availability and lowering blood pressure. Statin drugs interfere with Nox assembly to exert acute cardio-protective effects. (8) In addition to cardiovascular cells possessing Nox, resident macrophages, neutrophils, T-cells and platelets also express MR-activated Nox and contribute to vascular oxidative stress in disease. (9)
Simultaneous production of superoxide and NO can increase the production of peroxynitrite a million-fold, resulting in destruction of cellular components, dysfunction of critical cellular processes and disruption of signaling pathways that promote chronic hypertension and associated cardiovascular diseases. In chronic disease, peroxynitrite has further detrimental effects on redox balance by inducing additional superoxide production through mitochondrial electron transport chain disruption and by uncoupling eNOS. Peroxynitrite impairs free radical scavenging by decreasing the effectiveness of superoxide dismutase and glutathione anti-oxidant protection. Peroxynitrite damages DNA by oxidizing the nucleobase guanine and breaking the sugar-phosphate backbone to cause single-strand breaks. Guanine disruption results in mutagenesis and carcinogenesis while single-strand breaks cause the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) that repairs the DNA and promotes inflammation. When the DNA damage is severe, excessive PARP activation results in cell death through apoptosis or necrosis. (10)