Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors

Danyan Xu, Ning Li, Yuxia He, Valeriy Timofeyev, Ling Lu, Hsing Ju Tsai, In Hae Kim, Dipika Tuteja, Robertino Karlo P Mateo, Anil Singapuri, Benjamin B. Davis, Reginald Low, Bruce D. Hammock, Nipavan Chiamvimonvat

Research output: Contribution to journalArticle

157 Scopus citations

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-κB 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-κB-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-κB 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-κB activation.

Original languageEnglish (US)
Pages (from-to)18733-18738
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number49
DOIs
StatePublished - Dec 5 2006

Keywords

  • Epoxyeicosatrienoic acids
  • NF-κB

ASJC Scopus subject areas

  • Genetics
  • General

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    Xu, D., Li, N., He, Y., Timofeyev, V., Lu, L., Tsai, H. J., Kim, I. H., Tuteja, D., Mateo, R. K. P., Singapuri, A., Davis, B. B., Low, R., Hammock, B. D., & Chiamvimonvat, N. (2006). Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 103(49), 18733-18738. https://doi.org/10.1073/pnas.0609158103