4.4 Review

Soluble Epoxide Hydrolase Inhibitors and Heart Failure

Journal

CARDIOVASCULAR THERAPEUTICS
Volume 29, Issue 2, Pages 99-111

Publisher

WILEY-HINDAWI
DOI: 10.1111/j.1755-5922.2010.00150.x

Keywords

Cardiac hypertrophy; Cytochrome P450; Epoxyeicosatrienoic acids (EETs); Heart failure; Soluble epoxide hydrolase inhibitors

Funding

  1. Department of Veteran Affairs
  2. National Institutes of Health [HL85844, HL85727]
  3. NIEHS [R37 ES02710, P42 ES04699]
  4. NIEHS Center for Children's Environmental Health & Disease Prevention [P01 ES11269]
  5. UCDHS
  6. American Heart Association
  7. NIH [T32 HL86350]
  8. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL085727, T32HL086350, R01HL085844] Funding Source: NIH RePORTER
  9. NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES002710, P42ES004699, P01ES011269, R37ES002710] Funding Source: NIH RePORTER

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Cardiovascular disease remains one of the leading causes of death in the Western societies. Heart failure (HF) is due primarily to progressive myocardial dysfunction accompanied by myocardial remodeling. Once HF develops, the condition is, in most cases, irreversible and is associated with a very high mortality rate. Soluble epoxide hydrolase (sEH) is an enzyme that catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs), which are lipid mediators derived from arachidonic acid through the cytochrome P450 epoxygenase pathway. EETs have been shown to have vasodilatory, antiinflammatory, and cardioprotective effects. When EETs are hydrolyzed by sEH to corresponding dihydroxyeicosatrienoic acids, their cardioprotective activities become less pronounced. In line with the recent genetic study that has identified sEH as a susceptibility gene for HF, the sEH enzyme has received considerable attention as an attractive therapeutic target for cardiovascular diseases. Indeed, sEH inhibition has been demonstrated to have antihypertensive and antiinflammatory actions, presumably due to the increased bioavailability of endogenous EETs and other epoxylipids, and several potent sEH inhibitors have been developed and tested in animal models of cardiovascular disease including hypertension, cardiac hypertrophy, and ischemia/reperfusion injury. sEH inhibitor treatment has been shown to effectively prevent pressure overload- and angiotensin II-induced cardiac hypertrophy and reverse the pre-established cardiac hypertrophy caused by chronic pressure overload. Application of sEH inhibitors in several cardiac ischemia/reperfusion injury models reduced infarct size and prevented the progressive cardiac remodeling. Moreover, the use of sEH inhibitors prevented the development of electrical remodeling and ventricular arrhythmias associated with cardiac hypertrophy and ischemia/reperfusion injury. The data published to date support the notion that sEH inhibitors may represent a promising therapeutic approach for combating detrimental cardiac remodeling and HF.

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