Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo

doi:10.1073/pnas.0703229104

Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo

*Department of Physiology and Pathophysiology, Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, and
^§Institute of Cardiovascular Research, Peking University, Beijing 100083, China;
^†Division of Biomedical Sciences, University of California, Riverside, CA 92521; and
^‡Department of Entomology and Cancer Research Center, University of California, Davis, CA 95616

Contributed by Bruce D. Hammock, April 10, 2007 (received for review February 22, 2007)

Abstract

Epoxyeicosatrienoic acids (EETs), as metabolites of arachidonic acid, may function as antihypertensive and antiatherosclerotic mediators for vasculature. EETs are degraded by soluble epoxide hydrolase (sEH). Pharmacological inhibition and genetic ablation of sEH have been shown to increase the level of EETs, and treating angiotensin II (Ang II)-infused hypertension rats with sEH-selective inhibitors increased the levels of EETs, with attendant decrease in systolic blood pressure. To elucidate the mechanisms by which Ang II regulates sEH expression, we treated human umbilical vein endothelial cells (ECs) and bovine aortic ECs with Ang II and found increased sEH expression at both the mRNA and protein levels. Transient transfection assays showed that the activity of the human sEH promoter was increased in ECs in response to Ang II. Further analysis of the promoter region of the sEH gene demonstrated that treatment with Ang II, like overexpression of c-Jun/c-Fos, activates the sEH promoter through an AP-1-binding motif. The binding of c-Jun to the AP-1 site of the sEH promoter was confirmed by chromatin immunoprecipitation assays. In contrast, adenovirus overexpression of the dominant-negative mutant of c-Jun significantly attenuated the effects of Ang II on sEH induction. An elevated level of sEH was found in the aortic intima of both spontaneously hypertensive rats and Ang II-infused Wistar rats. Blocking Ang II binding to Ang II receptor 1 by losartan abolished the sEH induction. Thus, AP-1 activation is involved in the transcriptional up-regulation of sEH by Ang II in ECs, which may contribute to Ang II-induced hypertension.

Footnotes

^¶To whom correspondence may be addressed. E-mail: bdhammock{at}ucdavis.edu, john.shyy{at}ucr.edu, or zhuyi{at}hsc.pku.edu.cn
Author contributions: D.A., B.D.H., J.Y.-J.S., and Y.Z. designed research; D.A., Y.F., D.G., and H.T. performed research; N.W., C.T., and B.D.H. contributed new reagents/analytic tools; D.A., B.D.H., and Y.Z. analyzed data; and D.A., B.D.H., J.Y.-J.S., and Y.Z. wrote the paper.
Conflict of interest statement: B.D.H. founded Arête Therapeutics to develop sEH inhibitors.
Abbreviations:

EET,

epoxyeicosatrienoic acid;

EH,

epoxide hydrolase;

sEH,

soluble EH;

Ang II,

angiotensin II;

EC,

endothelial cell;

HUVEC,

human umbilical vein EC;

BAEC,

bovine aortic EC;

SHR,

spontaneously hypertensive rat;

AA,

arachidonic acid;

VSMC,

vascular smooth muscle cell;

DHET,

dihydroxyeicosatrienoic acid.