Androgen-sensitive hypertension associates with upregulated vascular CYP4A12-20-HETE synthase

Cheng Chia Wu, Shaojun Mei, Jennifer Cheng, Yan Ding, Adam Weidenhammer, Victor Garcia, Fan Zhang, Katherine Gotlinger, Vijaya L. Manthati, J R Falck, Jorge H. Capdevila, Michal L. Schwartzman

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Abstract

Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5a-dihydrotestosterone increased BP and induced both Cyp4a12 expression and 20-HETE levels in preglomerular microvessels. Administration of a 20-HETE antagonist prevented and reversed the effects of dihydrotestosterone on BP. Cyp4a14(-/-) mice, which exhibit androgen-sensitive hypertension in the male mice, produced increased levels of vascular 20-HETE; furthermore, administration of a 20-HETE antagonist normalized BP. To examine whether androgen-independent increases in 20-HETE are sufficient to cause hypertension, we studied Cyp4a12-transgenic mice, which express the CYP4A12-20-HETE synthase under the control of a doxycycline-sensitive promoter. Administration of doxycycline increased BP by 40%, and administration of a 20-HETE antagonist prevented this increase. Levels of CYP4A12 and 20-HETE in preglomerular microvessels of doxycycline-treated transgenic mice approximately doubled, correlating with increased 20-HETE-dependent sensitivity to phenylephrine-mediated vasoconstriction and with decreased acetylcholine- mediated vasodilation in the renal microvasculature. We observed a similar contribution of 20-HETE to myogenic tone in the mesenteric microvasculature. Taken together, these results suggest that 20-HETE both mediates androgeninduced hypertension and can cause hypertension independent of androgen.

Original languageEnglish (US)
Pages (from-to)1288-1296
Number of pages9
JournalJournal of the American Society of Nephrology
Volume24
Issue number8
DOIs
Publication statusPublished - Jul 31 2013

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ASJC Scopus subject areas

  • Nephrology

Cite this

Wu, C. C., Mei, S., Cheng, J., Ding, Y., Weidenhammer, A., Garcia, V., ... Schwartzman, M. L. (2013). Androgen-sensitive hypertension associates with upregulated vascular CYP4A12-20-HETE synthase. Journal of the American Society of Nephrology, 24(8), 1288-1296. https://doi.org/10.1681/ASN.2012070714