FIG. 5.
Nox and eNOS by Ang II in endothelial cells. Ang II stimulates production of O2•− by Nox1, Nox2, and Nox5 through the AT1R. Additionally, Ang II stimulates production of H2O2 directly through Nox4, and indirectly through the SOD-mediated conversion of O2•− produced by Nox1, 2, and 5. The O2•−-mediated oxidation and inactivation of the eNOS cofactor BH4 promotes uncoupling of eNOS, leading to eNOS-mediated production of O2•−. Additionally, H2O2 inhibits DHFR, an enzyme that catalyzes the conversion of BH2 to BH4, which further reduces BH4 bioavailability, leading to eNOS uncoupling. BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; CaM, calmodulin; DHFR, dihydrofolate reductase; eNOS, endothelial nitric oxide synthase; Fe, eNOS heme domain; H2O2, hydrogen peroxide; O2•−, superoxide; p22, p22 phox (Nox subunit); p40, p40 phox (Nox subunit); p47, p47 phox (Nox subunit); p67, p67 phox (Nox subunit); Rac, Rho-like GTPase Rac.