Published online before print September 23, 2004, doi: 10.1161/01.RES.0000146277.62128.6f
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Submitted on August 11, 2004
Revised on September 14, 2004
Accepted on September 16, 2004
Inhibition of Cytochrome P450
-Hydroxylase. A Novel Endogenous Cardioprotective Pathway
Kasem Nithipatikom ;
From the Department of Pharmacology and Toxicology (K.N., E.R.G., M.P.E., J.M.M., M.A.I., W.B.C., G.J.G.), Medical College of Wisconsin, Milwaukee, Wis; and the Departments of Biochemistry and Pharmacology (J.R.F.), University of Texas Southwestern Medical Center, Dallas, Tex.
* To whom correspondence should be addressed. E-mail: ggross{at}mcw.edu.
Cytochrome P450s (CYP) and their arachidonic acid (AA) metabolites have important roles in regulating vascular tone, but their function and specific pathways involved in modulating myocardial ischemia-reperfusion injury have not been clearly established. Thus, we characterized the effects of several selective CYP
-hydroxylase inhibitors and a CYP-hydroxylase metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), on the extent of ischemia-reperfusion injury in canine hearts. During 60 minutes of ischemia and particularly after 3 hours of reperfusion, 20-HETE was produced at high concentrations. A nonspecific CYP inhibitor, miconazole, and 2 specific CYP-hydroxylase inhibitors, 17-octadecanoic acid (17-ODYA) and N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly inhibited 20-HETE production during ischemia-reperfusion and produced a profound reduction in myocardial infarct size (expressed as a percent of the area at risk) (19.6±1.7% [control], 8.4±2.5% [0.96 mg/kg miconazole], 5.9±2.2% [0.28 mg/kg 17-ODYA], and 10.8±1.8% [0.40 mg/kg DDMS], P<0.05, respectively). Conversely, exogenous 20-HETE administration significantly increased infarct size (26.9±1.9%, P<0.05). Several CYP-hydroxylase isoforms, which are known to produce 20-HETE such as CYP4A1, CYP4A2, and CYP4F, were demonstrated to be present in canine heart tissue and their activity was markedly inhibited by incubation with 17-ODYA. These results indicate an important endogenous role for CYP-hydroxylases and in particular their product, 20-HETE, in exacerbating myocardial injury in canine myocardium. The full text of this article is available online at http://circres.ahajournals.org.
Key words: arachidonic acid metabolites • cytochrome p450 • 20-HETE • ischemia • reperfusion
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