Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo.
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.
Ai
Ding
D
Department of Physiology and Pathophysiology, Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Peking University, Beijing 100083, China.
Fu
Yi
Y
Guo
Deliang
D
Tanaka
Hiromasa
H
Wang
Nanping
N
Tang
Chaoshu
C
Hammock
Bruce D
BD
Shyy
John Y-J
JY
Zhu
Yi
Y
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004727:Endothelium / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D012995:Solubility; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D004851:Epoxide Hydrolases