Figure 1.

Potential pathways for redox and arginase modulation of vasomotor function. The low level of superoxide and hydrogen peroxide (H₂O₂) is essential for maintaining normal homeostasis of the endothelium to exert vasodilation in response to physiological stimulation. The excessive production of superoxide from the activated NAD(P)H oxidase and/or xanthine oxidase by insults from inflammatory cytokines, C-reactive protein (CRP), ischemia/reperfusion, oxidized low-density lipoprotein (Ox-LDL), or vasoconstrictor peptides such as angiotensin II (Ang II) and endothelin-1 (ET-1) (162–165) scavenges the released nitric oxide and subsequently forms peroxynitrite. The prolonged and elevated production of H₂O₂ from superoxide dismutase (SOD) suppresses NO production by up-regulating vascular arginase via p38 mitogen-activated protein kinase or c-Jun-N-terminal kinase (JNK) signaling following the hydroxyl radical (∙OH)- or protein kinase C (PKC)-mediated activation of Rho kinase. The upregulated arginase limits substrate L-arginine availability to nitric oxide synthase (eNOS) for nitric oxide synthesis and also uncouples eNOS to promote superoxide production. The production of nitric oxide from eNOS and prostacyclin (PGI₂) from cyclooxygenase (COX) and PGI₂ synthase (PGI₂-S) is inhibited by peroxynitrite due to uncoupling of eNOS and nitration of PGI₂-S (see text for details). Peroxynitrite also activates arginase and consequently reduces nitric oxide production. These redox events, in company with arginase upregulation, compromise endothelial function and thus augment vascular tone and reduce nitric oxide-mediated arteriolar dilation for blood flow recruitment and regulation. +, enhance/increase/upregulate; −, inhibit/reduce/downregulate.