NOX Isoforms and Reactive Oxygen Species in Vascular Health

Table 1

NADPH Oxidases: Primary Producers of Reactive Oxygen Species in Vasculature

Isoform	Tissue distribution	NOX complex	Regulation	Signaling	Function	Pathophysiology
NOX1	Colon epithelial cells; endothelial and VSMCs^a	NOX1, p22^phox, NOXO1^c, NOXA1^d	Shear stress, AngII^g, aldosterone, EGF, PDGF, PDI	RAC; PKC^d, MAPK, PKA	Constitutive low-level superoxide production; VSMC migration, proliferation, ECM; mitochondrial function	Hypertension, atherosclerosis, diabetes, and hyperc-holesterolemia
NOX2	Phagocytes; endothelial and VSMCs; cardiac, renal, and neural cells	NOX2^e, p22^phox, p47^phox, p40^phox p67^phox	Stretch, AngII, chemokines	RAC	Phagocytic respiratory burst; endothelial function and NO signaling; neointimal formation	NOX2 mutation in chronic granulomatous disease; experimental hypertension, atherosclerosis, ischemia-reperfusion injury
NOX4	Vascular cells^b, fibroblasts, osteoclasts, and adipocytes; Kidney	NOX4, p22^phox, (TKS4/5)^c, ^f	Poldip2^h, PDI, CLCN3; AngII, glucose, TNFα	(RAC)	VSMC growth and migration, angiogenesis; cardio-protective function; constitutive source of H₂O₂	Hypertension, atherosclerosis, diabetes, hypoxia-induced pulmonary hypertsnsion; senescence
NOX5	Testes, spleen, and lymphoid tissue; Kidney and vascular cells	None; NOX5 contains N-terminal calmodulin-like domain	[Ca²⁺]_i; Thrombin, PDGF, ANGII, ET-1	CREB	Endothelial cell/ VSMC proliferation, cell migration; angiogenesis	Atherosclerosis

↵a Abbreviations: VSMCs, vascular smooth muscle cells; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; PDI, protein disulfide isomerase; Poldip2, polymerase delta-interacting protein 2; CLCN3, chloride channel 3; TNF, tissue necrosis factor; ET-1, endothelin 1.
↵b Distribution may be determined by splice variants.
↵c NOXO1, or NOX organizer 1, is homologous to p47^phox. TKS4 and TKS5 have also been reported as members of the p47^phox-related organizer superfamily.
↵d NOXA1, or NOX activator 1, is homologous to p67^phox. NOXA1 appears to prevent NOX hyperactivity by engaging kinase pathways that inhibit interaction between NOX1 and RAC.
↵e NOX2, the prototypical family member, was formerly denoted gp91^phox, in recognition of its prominent glycosylation.
↵f Parentheses indicate preliminary data.
↵g AngII activates NOXs via AT₁ receptors through stimulation of signaling pathways involving SRC, RAS, PKC, PLD, and PLA₂.
↵h Associates with p22^phox; activates NOX4 to regulate focal adhesion turnover and VSMC migration, thus linking ROS production and cytoskeletal reorganization.