Faculty Collaboration Database

Epoxyeicosatrienoic acids in cardioprotection: ischemic versus reperfusion injury. Am J Physiol Heart Circ Physiol 2006 Aug;291(2):H537-42

Date

02/14/2006

Pubmed ID

16473964

DOI

10.1152/ajpheart.00071.2006

Scopus ID

2-s2.0-33746829910 (requires institutional sign-in at Scopus site)   82 Citations

Abstract

Cytochrome P-450 (CYP) epoxygenases and their arachidonic acid (AA) metabolites, the epoxyeicosatrienoic acids (EETs), have been shown to produce increases in postischemic function via ATP-sensitive potassium channels (K(ATP)); however, the direct effects of EETs on infarct size (IS) have not been investigated. We demonstrate that two major regioisomers of CYP epoxygenases, 11,12-EET and 14,15-EET, significantly reduced IS in dogs compared to control (22.1 +/- 1.8%), whether administered 15 min before 60 min of coronary occlusion (6.4 +/- 1.9%, 11,12-EET; and 8.4 +/- 2.4%, 14.15-EET) or 5 min before 3 h of reperfusion (8.8 +/- 2.1%, 11,12-EET; and 9.7 +/- 1.4%, 14,15-EET). Pretreatment with the epoxide hydrolase metabolite of 14,15-EET, 14,15-dihydroxyeicosatrienoic acid, had no effect. The protective effect of 11,12-EET was abolished (24.3 +/- 4.6%) by the K(ATP) channel antagonist glibenclamide. Furthermore, one 5-min period of ischemic preconditioning (IPC) reduced IS to a similar extent (8.7 +/- 2.8%) to that observed with the EETs. The selective CYP epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), did not block the effect of IPC. However, administration of MS-PPOH concomitantly with N-methylsulfonyl-12,12-dibromododec-11-enanide (DDMS), a selective inhibitor of endogenous CYP omega-hydroxylases, abolished the reduction in myocardial IS expressed as a percentage of area at risk (IS/AAR) produced by DDMS (4.6 +/- 1.2%, DDMS; and 22.2 +/- 3.4%, MS-PPOH + DDMS). These data suggest that 11,12-EET and 14,15-EET produce reductions in IS/AAR primarily at reperfusion. Conversely, inhibition of CYP epoxygenases and endogenous EET formation by MS-PPOH, in the presence of the CYP omega-hydroxylase inhibitor DDMS blocked cardioprotection, which suggests that endogenous EETs are important for the beneficial effects observed when CYP omega-hydroxylases are inhibited. Finally, the protective effects of EETs are mediated by cardiac K(ATP) channels.

Author List

Nithipatikom K, Moore JM, Isbell MA, Falck JR, Gross GJ

MESH terms used to index this publication - Major topics in bold

8,11,14-Eicosatrienoic Acid
Amides
Animals
Arachidonic Acid
Cardiotonic Agents
Coronary Circulation
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System
Dogs
Enzyme Inhibitors
Hemodynamics
Hydroxyeicosatetraenoic Acids
Mixed Function Oxygenases
Myocardial Ischemia
Myocardial Reperfusion Injury
Spectrometry, Mass, Electrospray Ionization
Sulfones