Vascular Nox4

Nox4, one of the 7 isoforms of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase family that generate reactive oxygen species, was first identified in the early 2000s in kidneys.1 Nox4 was originally described as an oxygen sensor and regulator of kidney cell growth and because of its renal abundance was termed “renox.”1 It soon became evident that Nox4 has a ubiquitous distribution and that it is expressed in many organ systems, such as the vasculature, and in many cell types including endothelial and vascular smooth muscle cells and in adventitial fibroblasts and adipocytes.2Article, see p 1217Nox4 is a unique Nox isoform. It localizes in the plasma membrane as well as intracellularly (focal adhesions, nucleus, mitochondria, endoplasmic reticulum), is constitutively active, is regulated at the gene level, associates with novel regulators such as Poldip2, and is influenced by vasoactive agonists (angiotensin II), physical factors (shear stress and flow), chemical changes (hypoxia), and microRNAs (miRNA25).2–4 Nox4 associates with p22phox for its activation, does not require interaction with classic NADPH oxidase cytosolic subunits (p47phox, p67phox, p40phox), and, unlike other Noxs, generates H2O2 in preference to O2−.2–4 Despite the fact that there has been enormous advancement in the understanding of Nox4 biochemistry and the mechanisms of Nox4 regulation, the functional significance and biological role of Nox4 remain elusive. Most studies investigating the (patho)physiology of Nox4 in the vascular system were conducted in cell-based systems, and those performed in animal studies were largely descriptive. Until very recently, mice in which Nox4 gene was knocked out were not available to study.Fewer than 250 original papers with key words “Nox4” and “Vascular” (PubMed search) have been published since the identification of Nox4 in 2001, indicating that the field is …