Circulation Research. 2002
Published online before print April 11, 2002, doi: 10.1161/01.RES.0000017727.35930.33
Published online before print April 11, 2002, doi: 10.1161/01.RES.0000017727.35930.33
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Submitted on January 15, 2002
Revised on March 5, 2002
Accepted on March 28, 2002
Inhibition of Vascular Smooth Muscle Cell Migration by Cytochrome P450 Epoxygenase-Derived Eicosanoids
Jianxin Sun ;
From the Vascular Medicine Research (J.S., J.K.L.) and Surgical Unit (X.S., M.S.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; and the Division of Intramural Research (A.B., D.C.Z.), NIH/NIEHS, Research Triangle Park, NC.
* To whom correspondence should be addressed. E-mail: jliao{at}rics.bwh.harvard.edu.
Vascular smooth muscle cell (SMC) migration and proliferation contribute to neointimal hyperplasia and restenosis after vascular injury. The epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess vasodilatory, antiinflammatory, and fibrinolytic properties. To determine whether these compounds also possess antimigratory and antiproliferative properties, we stimulated rat aortic SMCs with either 20% serum or platelet-derived growth factor (PDGF-BB, 20 ng/mL). In a concentration-dependent manner, treatment with EETs, particularly 11,12-EET, inhibited SMC migration through a modified transwell filter by 53% to 60%. EETs, however, have no inhibitory effects on PDGF-stimulated SMC proliferation. Adenoviral-mediated overexpression of the CYP isoform, CYP2J2, in SMCs also inhibited serum- and PDGF-induced SMC migration by 32% and 26%, respectively; both effects of which were reversed by the CYP inhibitors SKF525A or clotrimazole, but not by the KCa channel blocker, charybdotoxin, or the cyclooxygenase inhibitor, diclofenac. The effect of EETs correlated with increases in intracellular cAMP levels. Indeed, forskolin and 8-bromo-cAMP exert similar inhibitory effects on SMC migration as 11,12-EET and the effects of 11,12-EET were blocked by cAMP and protein kinase A (PKA) inhibitors. These findings indicate that EETs possess antimigratory effects on SMCs through the cAMP-PKA pathway and suggest that CYP epoxygenase-derived eicosanoids may play important roles in vascular disease and remodeling.
Key words: cytochrome P450 • epoxyeicosatrienoic acids • cAMP • protein kinase A • smooth muscle cells
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