Cytochrome P450 2C is an EDHF synthase in coronary arteries.
In most arterial beds a significant endothelium-dependent dilation to various stimuli persists even after inhibition of nitric oxide synthase and cyclo-oxygenase. This dilator response is preceded by an endothelium-dependent hyperpolarization of vascular smooth muscle cells, which is sensitive to a combination of the calcium-dependent potassium-channel inhibitors charybdotoxin and apamin, and is assumed to be mediated by an unidentified endothelium-derived hyperpolarizing factor (EDHF). Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by beta-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as EDHF-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP 2C8/34 antisense oligonucleotides results in decreased levels of CYP 2C and attenuates EDHF-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of EDHF-mediated relaxation in the porcine coronary artery, and CYP 2C8/34 fulfils the criteria for the coronary EDHF synthase.
Fisslthaler
B
B
Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.
Popp
R
R
Kiss
L
L
Potente
M
M
Harder
D R
DR
Fleming
I
I
Busse
R
R
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001685:Biological Factors / Q000096:biosynthesis*; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004730:Endothelium, Vascular / Q000201:enzymology; D004790:Enzyme Induction; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010105:Oxygenases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D014664:Vasodilation
D001685:Biological Factors; D016376:Oligonucleotides, Antisense; C067410:endothelium-dependent hyperpolarization factor; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000072467:Cytochrome P450 Family 2; C121871:cytochrome P-450 CYP2C8-34 (porcine); D015126:8,11,14-Eicosatrienoic Acid; D001920:Bradykinin