Nox4 Is a Protective Reactive Oxygen Species Generating Vascular NADPH Oxidase

Abstract

Ϫ ) react with nitric oxide (NO) to form peroxynitrite (ONOO Ϫ ), a process that limits NO availability, results in NO synthase (NOS) uncoupling, and, through the action of ONOO Ϫ , leads to protein and thiol oxidation as well as tyrosine nitration. 1 Hydrogen peroxide (H 2 O 2 ), the dismutation product of O 2 Ϫ , also elicits multiple effects, among them smooth muscle cell hypertrophy, activation of metalloproteinases, and, in higher concentrations, NOS inhibition by phosphorylation of tyrosine 657 through the redox-activated tyrosine kinase Pyk2. 2 Interestingly, H 2 O 2 also induces positive endothelial effects because it can activate protein kinase-G I␣ by thiol oxidation and subsequent dimerization. 3 Moreover, H 2 O 2 induces as well as activates endothelial NOS (eNOS). 4

Deficient angiogenesis in redox-dead Cys17Ser PKARIα knock-in mice

“…3e). Our observations are also consistent with recent observations that Nox4 KO mice are deficient in their angiogenic response to the same hind-limb ischaemia implemented to RIa redox-dead mice [9][10][11] . Discussion Nox-derived oxidants can act as powerful mediators of growth factor signalling 10,11,20 .…”

“…Recently three independent studies have specifically implicated Nox4 as an isozyme of NADPH oxidase that coupled to angiogenesis [9][10][11] . Consequently, we compared VEGF-induced RIa oxidation in the aorta from Nox4 knockout (KO) mice with littermate WTs, finding the former were substantially deficient (Fig.…”

“…Several studies have identified nicotinamide adenine dinucleotide phosphate-oxidase (Nox) enzymes as a major source of oxidants required for angiogenesis [9][10][11] . Although oxidase enzymes mediate angiogenesis, little is known about the molecular targets that sense and transduce the growth-stimulating 'oxidant signal'.…”

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

“…However, the fact that Nox4 produces more hydrogen peroxide than superoxide compared with other Nox oxidases (12, 50 -54) cannot be ignored. As a consequence, because hydrogen peroxide, unlike superoxide, does not react with NO, Nox4 is generally considered to be unlikely to significantly contribute to peroxynitrite generation and NOS uncoupling (51,(53)(54)(55)(56). This is reinforced by the recent observations that Nox4-derived hydrogen peroxide enhances eNOS activity and NO signaling.…”

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

“…Vascular Noxs have different functions in pathological conditions. Nox1 and Nox2 play a role in angiogenesis and atherosclerosis,3, 6 and Nox4 seems to be vasoprotective in ischemic and hypoxic conditions,10 but injurious in diabetes mellitus, where it promotes vascular fibrosis, diabetic nephropathy, and intravitreal neovascularization 11. Although Nox5 is expressed in mammalian vessels,12, 13, 14 there is a paucity of information on its role and biological significance in the cardiovascular system.…”