期刊
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
卷 90, 期 6, 页码 811-823出版社
CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
DOI: 10.1139/Y2012-082
关键词
epoxyeicosatrienoic acid; soluble epoxide hydrolase; ischemia-reperfusion; pmK(ATP) channels and sEH inhibitors
资金
- Heart and Stroke Foundation of Canada (HSFC)
- Alberta Innovates Health Solutions (AIHS)
- Boehringer Ingelheim Pharmaceuticals, Inc., USA
Epoxyeicosatrienoic acids (EETs) are active metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase enzyme (sEH) to dihydroxyeicosatrienoic acid. EETs are known to render cardioprotection against ischemia reperfusion (IR) injury by maintaining mitochondrial function. We investigated the effect of a novel sEH inhibitor (sEHi) in limiting IR injury. Mouse hearts were perfused in Langendorff mode for 40 min and subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with 0.0, 0.1, 1.0 and 10.0 mu mol.L-1 of the sEHi N-(2-chloro-4-methanesulfonyl-benzyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (BI00611953). Inhibition of sEH by BI00611953 significantly improved postischemic left-ventricular-developed pressure and reduced infarct size following IR compared with control hearts, and similar to hearts perfused with 11,12-EETs (1 mu mol.L-1) and sEH(-/-) mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 mu mol.L-1), or the plasma membrane K-ATP channels (pmK(ATP)) inhibitor (glibenclamide, 10 mu mol.L-1) abolished the improved recovery by BI00611953 (1 mu mol.L-1). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1 proportional to DNA binding, and delayed the loss of mitochondrial membrane potential (Delta Psi(m)) caused by anoxia-reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.
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