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National Institute of Environmental Health Sciences

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Publication Detail

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

Authors: Ai, Ding; Pang, Wei; Li, Nan; Xu, Ming; Jones, Paul D; Yang, Jun; Zhang, Youyi; Chiamvimonvat, Nipavan; Shyy, John Y-J; Hammock, Bruce D; Zhu, Yi

Published In Proc Natl Acad Sci U S A, (2009 Jan 13)

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 beta-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.

PubMed ID: 19126686 Exiting the NIEHS site

MeSH Terms: Angiotensin II/pharmacology*; Animals; Animals, Newborn; Cardiomegaly/chemically induced; Cardiomegaly/enzymology; Cardiomegaly/etiology*; Epoxide Hydrolases/analysis*; Epoxide Hydrolases/deficiency; Epoxide Hydrolases/genetics; Mice; Mice, Knockout; Myocardium/enzymology*; Myocytes, Cardiac/enzymology; Rats; Up-Regulation

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