Inhibition of cytochrome P450omega-hydroxylase: a novel endogenous cardioprotective pathway.

Kasem Nithipatikom, Eric R. Gross, Michael P. Endsley, Jeannine M. Moore, Marilyn A. Isbell, John R. Falck, William B. Campbell, Garrett J. Gross

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

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 CYPomega-hydroxylase inhibitors and a CYPomega-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 CYPomega-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 CYPomega-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 CYPomega-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.

Original languageEnglish (US)
Pages (from-to)e65-71
JournalCirculation research
Volume95
Issue number8
StatePublished - Oct 15 2004

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ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Nithipatikom, K., Gross, E. R., Endsley, M. P., Moore, J. M., Isbell, M. A., Falck, J. R., Campbell, W. B., & Gross, G. J. (2004). Inhibition of cytochrome P450omega-hydroxylase: a novel endogenous cardioprotective pathway. Circulation research, 95(8), e65-71.