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Vol. 60, Issue 2, 310-320, August 2001
Division of Intramural Research, National Institute of
Environmental Health Sciences, National Institutes of Health, Research
Triangle Park, North Carolina (B.Y., L.G., S.D., R.P.M., D.C.Z.);
Department of Biochemistry, University of Texas Southwestern Medical
Center, Dallas, Texas (J.R.F.); and Cardiovascular Division, Brigham
and Women's Hospital and Harvard Medical School, Boston, Massachusetts
(J.K.L.)
CYP2J2 is abundant in human heart and its arachidonic acid metabolites,
the epoxyeicosatrienoic acids (EETs), have potent vasodilatory,
antiinflammatory and cardioprotective properties. This study was
designed to examine the role of CYP2J2 in hypoxia-reoxygenation-induced injury in cultured bovine aortic endothelial cells (BAECs). Early passage BAECs were exposed to 24-h hypoxia followed by 4-h
reoxygenation (HR). HR resulted in cell injury, as indicated by
significant increases in lactate dehydrogenase (LDH) release and trypan
blue stained cells (p < 0.01) and was associated
with a decrease in CYP2J2 protein expression. Transfection of BAECs
with the CYP2J2 cDNA resulted in increased CYP2J2 expression and
arachidonic acid epoxygenase activity, compared with cells transfected
with an irrelevant green fluorescent protein (GFP) cDNA. HR induced
significant injury in GFP-transfected BAECs, as indicated by increases
in LDH release and trypan blue-stained cells (p < 0.01); however, the HR-induced injury was markedly attenuated in
CYP2J2-transfected cells (p < 0.01). HR increased
cellular 8-iso-prostaglandin F2
(p < 0.05), and decreased eNOS expression, L-arginine uptake
and conversion, and nitrite production (p < 0.01)
in GFP-transfected BAECs. CYP2J2 transfection attenuated the HR-induced
increase in 8-iso-prostaglandin F2
(p < 0.05) and decreased the amount of
extracellular superoxide detected by cytochrome c
reduction under normoxic conditions (p < 0.05) but
did not significantly affect HR-induced decreases in eNOS expression,
L-arginine uptake and conversion, and nitrite production.
Treatment of BAECs with synthetic EETs and/or epoxide hydrolase
inhibitors also showed protective effects against HR injury
(p < 0.05). These observations suggest: (1) HR
results in endothelial injury and decreased CYP2J2 expression; (2)
transfection with the CYP2J2 cDNA protects against HR injury; and (3)
the cytoprotective effects of CYP2J2 may be mediated, at least in part,
by antioxidant effects.
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