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)