NADPH Oxidases in the Heart

The recently discovered protein family of NADPH oxidases (NOX) is a group of transmembrane proteins that generate reactive oxygen species (ROS) by transferring electrons from NADPH onto molecular oxygen. The NOX proteins are the catalytic subunits that assemble with several regulatory subunits to form the catalytically active enzyme complex. Of the regulatory subunits exist several isoforms that are differentially expressed in a wide range of tissues. In relation to the heart, low NOX1 expression has been described in the coronary vascular system, NOX2 expression in cardiomyocytes, vascular smooth muscle (VSMCs) and endothelial cells, and NOX4 seems to be present in VSMCs, fibroblasts and endothelial cells. While the prototypical NOX2 in phagocytes generates high bursts of superoxide that are needed to kill off invading pathogens, the other members of this family, as well as NOX2 in nonphagocytic tissues, are responsible for the generation of lower levels of ROS that are essential for cell signalling. Since the first demonstration of the basic principle of NADPH-oxidase-dependent redox signalling some ten years ago, NADPH-oxidase-derived ROS have been implicated in all major signalling pathways in most, if not all, tissue types. In the heart, ROS have been shown to play a role in cell proliferation, hypertrophy, apoptosis, differentiation and endothelial activation and adhesivity. Not surprisingly, therefore, NADPH oxidases have been implicated in the pathophysiologies of diabetes, hypertension, atherosclerosis, cardiac hypertrophy, heart failure, preconditioning and acute myocardial infarction, both by dysregulation of redox-based signalling pathways and by oxidative modification of a wide range of biomolecules. This review will briefly present the different NOX-family members and summarize our current knowledge concerning their regulation. Thereafter, we will give an overview of the expression patterns of the NOX-family members in the heart, both in health and disease, and will review their role in the (patho) physiology of the heart. Finally the present-day therapeutic opportunities in the form of the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, will be critically assessed.