Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization.
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 H2O2 is an EDHF in mesenteric arteries of mice and humans and in porcine coronary microvessels. However, the mechanism for the endothelial production of H2O2 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 H2O2 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.
Morikawa
Keiko
K
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
Shimokawa
Hiroaki
H
Matoba
Tetsuya
T
Kubota
Hiroshi
H
Akaike
Takaaki
T
Talukder
M A Hassan
MA
Hatanaka
Makoto
M
Fujiki
Takako
T
Maeda
Hiroshi
H
Takahashi
Shosuke
S
Takeshita
Akira
A
D000818:Animals; D000838:Anions; D001685:Biological Factors / Q000502:physiology*; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D004594:Electrophysiology; D004727:Endothelium / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry; D008297:Male; D051379:Mice; D008833:Microcirculation; D009569:Nitric Oxide / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D000838:Anions; D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D013481:Superoxides; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase