Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: Insight gained using metabolomic approaches

Li, Ning; Liu, Jun-Yan; Timofeyev, Valeriy; Qiu, Hong; Hwang, Sung Hee; Tuteja, Dipika; Lu, Ling; Yang, Jun; Mochida, Hideki; Low, Reginald; Hammock, Bruce D.; Chiamvimonvat, Nipavan

doi:10.1016/j.yjmcc.2009.08.017

« PreviousJournal of Molecular and Cellular Cardiology
Volume 47, Issue 6 , Pages 835-845, December 2009

Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: Insight gained using metabolomic approaches

Ning Li
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
Jun-Yan Liu
- Department of Entomology and UCD Cancer Center, University of California, Davis, CA, USA
Valeriy Timofeyev
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
Hong Qiu
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
Sung Hee Hwang
- Department of Entomology and UCD Cancer Center, University of California, Davis, CA, USA
Dipika Tuteja
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
Ling Lu
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
Jun Yang
- Department of Entomology and UCD Cancer Center, University of California, Davis, CA, USA
Hideki Mochida
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
Reginald Low
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
Bruce D. Hammock
- Department of Entomology and UCD Cancer Center, University of California, Davis, CA, USA
Nipavan Chiamvimonvat
- Division of Cardiovascular Medicine, University of California, Davis, Davis, CA, USA
- Department of Veterans Affairs, Northern California Health Care System, Mather, CA, USA
- Corresponding author. Division of Cardiovascular Medicine, University of California, Davis, One Shields Avenue, GBSF 6315, Davis, CA 95616, USA. Fax: +1 530 752 3264.

Received 23 July 2009; accepted 8 August 2009. published online 01 September 2009.

Abstract

Myocardial infarction (MI) leading to myocardial cell loss represents one of the common causes leading to cardiac failure. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase (sEH) inhibitors in cardiac hypertrophy. sEH catalizes the conversion of epoxyeicosatrienoic acids (EETs) to form the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are products of cytochrome P450 epoxygenases that have vasodilatory properties. Additionally, EETs inhibit the activation of nuclear factor (NF)-κB-mediated gene transcription. Motivated by the potential to uncover a new class of therapeutic agents for cardiovascular diseases which can be effectively used in clinical setting, we directly tested the biological effects of sEH inhibitors (sEHIs) on the progression of cardiac remodeling using a clinically relevant murine model of MI. We demonstrated that sEHIs were highly effective in the prevention of progressive cardiac remodeling post MI. Using metabolomic profiling of the inflammatory lipid mediators, we documented a significant decrease in EETs/DHETs ratio in MI model predicting a heightened inflammatory state. Treatment with sEHIs resulted in a change in the pattern of lipid mediators from one of inflammation towards resolution. Moreover, the oxylipin profiling showed a striking parallel to the changes in inflammatory cytokines in this model. Our study provides evidence for a possible new therapeutic strategy to improve cardiac function post MI.

Keywords: Soluble epoxide hydrolase, Soluble epoxide hydrolase inhibitors, Myocardial infarction, Epoxyeicosatrienoic acids, Oxylipin profiling