NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies

Abstract

NADPH oxidase family enzymes (or NOXs) are the major sources of reactive oxygen species (ROS) that are implicated in the pathophysiology of many cardiovascular diseases. These enzymes appear to be especially important in the modulation of redox-sensitive signalling pathways that underlie key cellular functions such as growth, differentiation, migration and proliferation. Seven distinct members of the family have been identified of which four (namely NOX1, 2, 4 and 5) may have cardiovascular functions. In this article, we review our current understanding of the roles of NOX enzymes in several common cardiovascular disease states, with a focus on data from genetic studies and clinical data where available.

Fig. 1

Schematic representation of NOX1, NOX2, NOX4 and NOX5 oxidases. NOX1 and NOX2 require association with cytosolic regulatory subunits for their activation, as indicated

Fig. 2

Contrasting vascular effects of NOX1/2 versus NOX4. a NOX1 and NOX2 promote endothelial dysfunction and vascular remodelling, at least in part through O₂ ^·−-dependent inactivation of NO. NOX4 on the other hand enhances endothelial-dependent relaxation through H₂O₂-dependent hyperpolarization. These effects may contribute to changes in BP. b Effects of endothelial-specific NOX4 overexpression on ambulatory BP measured by telemetry (top) and acetylcholine (Ach)-induced relaxation in isolated aortic rings. Tg transgenic mice; SBP systolic BP; DBP diastolic BP. ***P < 0.001. Reproduced with permission from [98]

Fig. 3

Protective role of NOX4 during pressure overload cardiac hypertrophy. a Representative images from NOX4 knockout mice or wild-type littermates (WT) subjected to pressure overload by aortic constriction. Panel A shows whole heart sections (scale bar 2 mm); panel B shows myocardial sections stained with wheat-germ agglutinin to show cardiomyocyte area; panel C shows myocardial sections stained with Picrosirius Red to show fibrosis (scale bars 20 μm). NOX4 KO mice developed greater hypertrophy, fibrosis and remodelling than WT after pressure overload. Reproduced with permission from Zhang et al. [122]. b Schematic illustrating the mechanism underlying protective effects of NOX4. Upregulation of NOX4 enhances HIF1 activation and the release of VEGF which exerts paracrine effects to promote preservation of myocardial capillary density

Fig. 4

Effect of NOX2 deletion on post-MI remodelling. Representative M-mode echocardiographic images from NOX2 knockout mice or wild-type littermates (WT) subjected to left coronary ligation or sham ligation surgery. The extent of LV dilatation and reduction in fractional shortening 4 weeks after MI is significantly reduced in the NOX2 knockout group compared to WT. Reproduced with permission from Looi et al. [81]