NADPH oxidase in the heart

Increasingly clear that NADPH oxidases play a pivotal role in cardiovascular physiology and pathology. Under physiological conditions, the Nox-derived superoxide and hydrogen peroxide play a relevant part in cardiovascular homeostasis, as signaling molecules, by regulating diverse functions, including differentation, proliferation and vascular tone. In pathological circumstances NADPH oxidases are also crucial for inflammatory responses and apoptosis, and growing evidence shows, that dysregulation or upregulation of Nox enzymes can promote the development of cardiovascular diseases. The most important Nox isoforms, which are expressed in the heart, are Nox1, Nox2, Nox4 and Nox5. Nox1 is highly expressed in vascular smooth muscle cells (VSMCs) and several studies suggested that its main role is in proliferation, migration, and configuration of the formation of neointimal after vascular injury. Nox2 is expressed in endothelial cells, fibroblasts and cardiomyocytes, and its role is to regulate cardiac and endothelial functions. Several vasoactive stimuli upregulate Nox2, such as angiotensin II, atrial natiuretic peptide, shear stress. This isoform in the heart is described as a vascular tone, inflammation, endothelial cell proliferation and migration, and angiogenesis stimulating enzyme. Nox4 is the most highly expressed NADPH oxidase isoform in all cell types of the heart and vasculature, but its role is still disputed. Nox4 is a constitutively active isoform, which generates higher amount of hydrogen peroxide rather than superoxide. Nox4-derived H₂O₂ seems to act as an endothelium-derived hyperpolarizing factor, which contributes to vasodilation. Ray et al proved that Nox4 overexpression in mice endothelium increases endothelium-dependent relaxation and lowers the blood pressure in vivo which are attributable to H₂O₂ production. These effects contrast markedly with those reported for Nox1 and Nox2, which involve superoxide-mediated inactivation of nitric oxide. Nox5 is expressed in VMSCs and endothelial cells, and interestingly this isoform is not expressed in rodents. Montezano et al. found that Nox5 isoforms activation is formed by the induction of Ang II and endothelin 1 through Ca²⁺-calmodulin dependent manner.

The incorrect operation of the NADPH oxidases are described to contribute to  the development of cardiovascular diseases, including atherosclerosis, hypertension, heart failure, myocardial infaction (MI) and remodeling, cardiac fibrosis and left ventricular hypertrophy. Heart failure is ever-growing cause of death in our days. It appears prevalent in patients with myocardial infarction and myocardial remodelling, which contributes to heart failure. Zhao et al. have found, that ROS and oxidative stress following MI has an emergent role in cardiac remodelling, and it is well documented, that after myocardial infarction, NADPH oxidases are significantly higher expressed in the infarcted myocardium. In atherosclerotic plaques, Sorescu et al. have found significantly increased levels of Nox2 and O^2-. Luo et al. have found that administration of a NADPH oxidase inhibitor, apocynin, decrease the ischemia/reperfusion induced myocardial injury, thereby reduces cell death and ROS production.

Furthermore Noxs may act as a sensor, and the Nox-derived ROS as a transducer for hypoxia, therefore they are functional at low partial O₂ pressure. Nox4 is the major oxygen sensor and regulates erythropoietin (EPO) expression in the kidney. In cardiac pathology, Zhang et al. have proven in Nox4-null mouse model and Nox4 transgenic model that Nox4 plays a pivotal cardioprotective role in hypertrophy by mediating angiogenesis. To investigate these functional roles of Nox4 during the cardiac response to stress, genetically deleted Nox4 or cardiomyocyte-targeted overexpression of Nox4 mice were developed. 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 the 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 and a key determinant of cardiac adaptation to overload stress