Soluble epoxide hydrolase plays an essential role in angiotensin II-induced cardiac hypertrophy

doi:10.1073/pnas.0811022106

Soluble epoxide hydrolase plays an essential role in angiotensin II-induced cardiac hypertrophy

^aDepartment of Physiology and Pathophysiology and
^bInstitute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Health Science Center, Ministry of Education, Peking University, Beijing 100083, China;
^cDepartment of Entomology and Cancer Research Center and
^eDepartment of Cardiovascular Medicine, University of California Medical Center, University of California, Davis, CA 95616;
^dInternational Flavors and Fragrances Inc., 1515 State Highway 36, Union Beach, NJ 07735; and
^fDivision of Biomedical Sciences, University of California, Riverside, CA 92521

Contributed by Bruce D. Hammock, November 13, 2008 (received for review August 13, 2008)

Abstract

Pathophysiological cardiac hypertrophy is one of the most common causes of heart failure. Epoxyeicosatrienoic acids, hydrolyzed and degraded by soluble epoxide hydrolase (sEH), can function as endothelium-derived hyperpolarizing factors to induce dilation of coronary arteries and thus are cardioprotective. In this study, we investigated the role of sEH in two rodent models of angiotensin II (Ang II)-induced cardiac hypertrophy. The protein level of sEH was elevated in the heart of both spontaneously hypertensive rats and Ang II-infused Wistar rats. Blocking the Ang II type 1 receptor with losartan could abolish this induction. Administration of a potent sEH inhibitor (sEHI) prevented the pathogenesis of the Ang II-induced hypertrophy, as demonstrated by decreased left-ventricular hypertrophy assessed by echocardiography, reduced cardiomyocyte size, and attenuated expression of hypertrophy markers, including atrial natriuretic factor and β-myosin heavy chain. Because sEH elevation was not observed in exercise- or norepinephrine-induced hypertrophy, the sEH induction was closely associated with Ang II-induced hypertrophy. In vitro, Ang II upregulated sEH and hypertrophy markers in neonatal cardiomyocytes isolated from rat and mouse. Expression of these marker genes was elevated with adenovirus-mediated sEH overexpression but decreased with sEHI treatment. These results were supported by studies in neonatal cardiomyocytes from sEH^−/− mice. Our results suggest that sEH is specifically upregulated by Ang II, which directly mediates Ang II-induced cardiac hypertrophy. Thus, pharmacological inhibition of sEH would be a useful approach to prevent and treat Ang II-induced cardiac hypertrophy.

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Footnotes

¹To whom correspondence should be addressed. E-mail: bdhammock{at}ucdavis.edu or zhuyi{at}hsc.pku.edu.cn
Author contributions: D.A., W.P., N.C., B.D.H., and Y. Zhu designed research; D.A., W.P., N.L., M.X., and J.Y. performed research; D.A., W.P., and Y. Zhu analyzed data; P.D.J., Y. Zhang, J.Y.-J.S., B.D.H., and Y. Zhu contributed new reagents/analytic tools; and D.A., J.Y.-J.S., B.D.H., and Y. Zhu wrote the paper.
Conflict of interest statement: P.D.J., N.C., and B.D.H. authored University of California patents in this area. B. D. Hammock founded Arete Therapeutics to evaulate inhibitors of the soluble epoxide hydrolase as therapeutic agents. Arete has licensed UC IP in this area. None of the authors received funding for this work from Arete Therepeutics, and Arete Therapeutics scientists did not contribute to these studies.
This article contains supporting information online at www.pnas.org/cgi/content/full/0811022106/DCSupplemental.