NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis

Abstract

Cardiac failure occurs when the heart fails to adapt to chronic stresses. Reactive oxygen species (ROS)-dependent signaling is implicated in cardiac stress responses, but the role of different ROS sources remains unclear. Here we report that NADPH oxidase-4 (Nox4) facilitates cardiac adaptation to chronic stress. Unlike other Nox proteins, Nox4 activity is regulated mainly by its expression level, which increases in cardiomyocytes under stresses such as pressure overload or hypoxia. To investigate the functional role of Nox4 during the cardiac response to stress, we generated mice with a genetic deletion of Nox4 or a cardiomyocyte-targeted overexpression of Nox4. Basal cardiac function was normal in both models, but Nox4-null animals developed exaggerated contractile dysfunction, hypertrophy, and cardiac dilatation during exposure to chronic overload whereas Nox4-transgenic mice were protected. Investigation of mechanisms underlying this protective effect revealed a significant Nox4-dependent preservation of myocardial capillary density after pressure overload. Nox4 enhanced stress-induced activation of cardiomyocyte hypoxia inducible factor 1 and the release of vascular endothelial growth factor, resulting in increased paracrine angiogenic activity. These data indicate that cardiomyocyte Nox4 is a unique inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress. Our results also have wider relevance to the use of nonspecific antioxidant approaches in cardiac disease and may provide an explanation for the failure of such strategies in many settings.cardiac remodeling | hypoxia inducible factor | reactive oxygen species

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

“…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 . However, the targets of these oxidants and the mechanism by which they enhance vessel growth have remained elusive.…”

“…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'.…”

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…Nox4-derivd ROS has also been suggested in cellular senescence and aging (104) and in insulin-mediated differentiation of adipocytes (177). Recent studies demonstrated that Nox4 may actually have protective effects, possibly through Nox4-derived H 2 O 2 , which may act as a vasodilator in some vascular beds (164,238). This could explain why mice with targeted endothelial Nox4 overexpression have lower blood pressure and improved endothelium-dependent vasodilation versus wild-type controls (164).…”

Vascular Nox4

“…In fact, in some conditions, even the same approach yields divergent results. Mice in which Nox4 was targeted in a cardiac-specific manner demonstrated that Nox4 is both protective 21 and injurious 22 in models of cardiac overload.…”