Abstract
The heart relies on complex mechanisms that provide adequate myocardial oxygen supply in order to maintain its contractile function. At the cellular level, oxygen undergoes one electron reduction to superoxide through the action of different types of oxidases (e.g. xanthine oxidases, uncoupled nitric oxide synthases, NADPH oxidases or NOX). Locally generated oxygen-derived reactive species (ROS) are involved in various signaling pathways including cardiac adaptation to different types of physiological and pathophysiological stresses (e.g. hypoxia or overload). The specific effects of ROS and their regulation by oxidases are dependent on the amount of ROS generated and their specific subcellular localization. The NOX family of NADPH oxidases is a main source of ROS in the heart. Seven distinct Nox isoforms (NOX1–NOX5 and DUOX1 and 2) have been identified, of which NOX1, 2, 4 and 5 have been characterized in the cardiovascular system. For the purposes of this review, we will focus on the effects of NADPH oxidase 4 (NOX4) in the heart.
Highlights
The heart relies on complex mechanisms that provide adequate myocardial oxygen supply in order to maintain its contractile function
NOX4D is the only variant that has been found to be functionally active in terms of ROS generation, despite lacking putative transmembrane regions as it retains the NADPH- and FAD-binding domains required for electron transfer activity
The functional benefits of increased NADPH oxidase 4 (NOX4) levels in the pressure-overloaded heart were first identified by Zhang et al when they employed loss- and gain-of-function NOX4 mouse models and reported that, following abdominal aortic banding in mice, NOX4 exerts its protective effects through a mechanism involving paracrine enhancement of capillary density [13]
Summary
Poldip and transcriptional regulation fibroblasts, vascular smooth muscle cells. Vascular smooth muscle and endothelial cells (absent in rodents) rs1836882 in the NOX4 gene modulates associations between dietary caloric intake and ROS levels in peripheral blood mononuclear cells [5]. The exact location of NOX4 remains largely debated, with reports positioning the enzyme in the endoplasmic reticulum, mitochondria, plasma membrane and nucleus [10, 11] The reasons for these disparities may reflect the cell-specific differences in the functions of NOX4 in the different cell types studied, the fact that NOX4 localization might be transitory based on its interactions with certain targets [12] and/or the quality of research tools and approaches employed. Contrasting observations were reported by the Sadoshima laboratory when they reported the detrimental effects of NOX4 in the overloaded heart due to increased mitochondrial ROS production and damage [14] While these differences may be attributed to the type and severity of overload studied and means via which NOX4 levels were manipulated, the protective effects of NOX4 have been since corroborated in cardiomyocyteand endothelial-specific NOX4-null mice, where transaortic constriction was associated with more severe cardiac function and remodeling in the NOX4-deficient mice [15]. Further studies are required to delineate some of these discrepancies on the exact role of NOX4 during IR injury in the heart
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