title: Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors.
abstract: Sustained cardiac hypertrophy represents one of the most common causes leading to cardiac failure. There is emerging evidence to implicate the involvement of NF-kappaB in the development of cardiac hypertrophy. However, several critical questions remain unanswered. We tested the use of soluble epoxide hydrolase (sEH) inhibitors as a means to enhance the biological activities of epoxyeicosatrienoic acids (EETs) to treat cardiac hypertrophy. sEH catalyzes the conversion of EETs to form the corresponding dihydroxyeicosatrienoic acids. Previous data have suggested that EETs may inhibit the activation of NF-kappaB-mediated gene transcription. We directly demonstrate the beneficial effects of several potent sEH inhibitors (sEHIs) in cardiac hypertrophy. Specifically, we show that sEHIs can prevent the development of cardiac hypertrophy using a murine model of pressure-induced cardiac hypertrophy. In addition, sEHIs reverse the preestablished cardiac hypertrophy caused by chronic pressure overload. We further demonstrate that these compounds potently block the NF-kappaB activation in cardiac myocytes. Moreover, by using in vivo electrophysiologic recordings, our study shows a beneficial effect of the compounds in the prevention of cardiac arrhythmias that occur in association with cardiac hypertrophy. We conclude that the use of sEHIs to increase the level of the endogenous lipid epoxides such as EETs may represent a viable and completely unexplored avenue to reduce cardiac hypertrophy by blocking NF-kappaB activation.
authors.affiliation: Division of Cardiovascular Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Danyan
authors.initials: D
authors.lastname: Xu
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yuxia
authors.initials: Y
authors.lastname: He
authors.forename: Valeriy
authors.initials: V
authors.lastname: Timofeyev
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Hsing-Ju
authors.initials: HJ
authors.lastname: Tsai
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Kim
authors.forename: Dipika
authors.initials: D
authors.lastname: Tuteja
authors.forename: Robertino Karlo P
authors.initials: RK
authors.lastname: Mateo
authors.forename: Anil
authors.initials: A
authors.lastname: Singapuri
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Davis
authors.forename: Reginald
authors.initials: R
authors.lastname: Low
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases