Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors

doi:10.1073/pnas.0609158103

Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors

*Division of Cardiovascular Medicine,
^§Center for Health and the Environment, and
^‡Department of Entomology and Cancer Research Center, University of California, Davis, CA 95616;
^‖Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655; and
^†Department of Cardiology, Internal Medicine, Xiangya Second Hospital, Central-South University, Changsha, Hunan Province 410007, China

Contributed by Bruce D. Hammock, October 17, 2006 (received for review June 19, 2006)

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.

Footnotes

^¶To whom correspondence may be addressed. E-mail: bdhammock{at}ucdavis.edu
**To whom correspondence may be addressed at:
Division of Cardiovascular Medicine, University of California, One Shields Avenue, GBSF 6315, Davis, CA 95616.
E-mail: nchiamvimonvat{at}ucdavis.edu
Author contributions: D.X., N.L., B.D.H., and N.C. designed research; D.X., N.L., Y.H., V.T., L.L., D.T., R.K.P.M., A.S., B.B.D., and N.C. performed research; H.-J.T., I.-H.K., R.L., and B.D.H. contributed new reagents/analytic tools; D.X., N.L., Y.H., V.T., L.L., B.D.H., and N.C. analyzed data; and B.D.H. and N.C. wrote the paper.
Conflict of interest statement: N.C. and B.D.H. have filed patents for the University of California for sEH and cardiac hypertrophy therapy. B.D.H. founded Arête Therapeutics to move sEH inhibitors into clinical trials.
Abbreviations:

Ang II,

angiotensin II;

ANF,

atrial natriuretic factor;

APEU,

1-adamantan- 3-(5-(2-(2-ethylethoxy)ethoxy)pentyl)urea;

AUDA,

12-(3-adamantan-1-yl-ureido)-dodecanoic acid;

DHET,

dihydroxyeicosatrienoic acid;

EET,

epoxyeicosatrienoic acid;

LV-ESD,

left ventricular end systolic dimension;

MHC,

myosin heavy chain;

sEH,

soluble epoxide hydrolase;

sEHI,

sEH inhibitor;

TAC,

thoracic aortic constriction.