Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization

Abstract

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, NO, and endothelium-derived hyperpolarizing factor (EDHF).We have recently identified that endothelium-derived H 2 O 2 is an EDHF in mesenteric arteries of mice and humans and in porcine coronary microvessels.However, the mechanism for the endothelial production of H 2 O 2 as an EDHF remains to be elucidated.In this study, we tested our hypothesis that Cu,Zn-superoxide dismutase (Cu,Zn-SOD) plays a pivotal role in endothelium-dependent hyperpolarization, using control and Cu,Zn-SOD -/-mice.In mesenteric arteries, EDHF-mediated relaxations and hyperpolarizations were significantly reduced in Cu,Zn-SOD -/-mice with no inhibitory effect of catalase, while endothelium-independent relaxations and hyperpolarizations were preserved.Endothelial H 2 O 2 production also was significantly reduced in Cu,Zn-SOD -/-mice.In Langendorff isolated heart, bradykinin-induced increase in coronary flow was significantly reduced in Cu,Zn-SOD -/-mice, again with no inhibitory effect of catalase.The exogenous SOD mimetic tempol significantly improved EDHF-mediated relaxations and hyperpolarizations and coronary flow response in Cu,Zn-SOD -/-mice.These results prove the novel concept that endothelial Cu,Zn-SOD plays an important role as an "EDHF synthase" in mice, in addition to its classical role to scavenge superoxide anions.