Eicosapentaenoic acid (EPA) induces Ca(2+)-independent activation and translocation of endothelial nitric oxide synthase and endothelium-dependent vasorelaxation.
Eicosapentaenoic acid (EPA), but not its metabolites (docosapentaenoic acid and docosahexaenoic acid), stimulated nitric oxide (NO) production in endothelial cells in situ and induced endothelium-dependent relaxation of bovine coronary arteries precontracted with U46619. EPA induced a greater production of NO, but a much smaller and more transient elevation of intracellular Ca(2+) concentration ([Ca(2+)]i), than did a Ca(2+) ionophore (ionomycin). EPA stimulated NO production even in endothelial cells in situ loaded with a cytosolic Ca(2+) chelator 1,2-bis-o-aminophenoxythamine-N',N',N'-tetraacetic acid, which abolished the [Ca(2+)]i elevations induced by ATP and EPA. The EPA-induced vasorelaxation was inhibited by N(omega)-nitro-L-arginine methyl ester. Immunostaining analysis of endothelial NO synthase (eNOS) and caveolin-1 in cultured endothelial cells revealed eNOS to be colocalized with caveolin in the cell membrane at a resting state, while EPA stimulated the translocation of eNOS to the cytosol and its dissociation from caveolin, to an extent comparable to that of the eNOS translocation induced by a [Ca(2+)]i-elevating agonist (10 microM bradykinin). Thus, EPA induces Ca(2+)-independent activation and translocation of eNOS and endothelium-dependent vasorelaxation.
Omura
M
M
Second Department of Internal Medicine, School of Medicine, Yamaguchi University, Ube, Japan.
Kobayashi
S
S
Mizukami
Y
Y
Mogami
K
K
Todoroki-Ikeda
N
N
Miyake
T
T
Matsuzaki
M
M
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D014664:Vasodilation / Q000187:drug effects*
D009569:Nitric Oxide; D004533:Egtazic Acid; D015118:Eicosapentaenoic Acid; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium