Androgen-dependent hypertension is mediated by 20-hydroxy-5,8,11,14- eicosatetraenoic acid-induced vascular dysfunction: Role of inhibitor of κb kinase

Cheng Chia Wu, Jennifer Cheng, Frank Fan Zhang, Katherine H. Gotlinger, Mukul Kelkar, Yilun Zhang, Jawahar L. Jat, John R. Falck, Michal L. Schwartzman

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Increased vascular synthesis of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) is associated with increased vascular contraction, endothelial dysfunction, and endothelial activation; all are believed to account for 20-HETE prohypertensive properties. We demonstrated previously that the 20-HETE-dependent inhibition of NO production is mediated through inhibitor of κB kinase (IKK), suggesting a cross-talk between 20-HETE-mediated endothelial dysfunction and activation. In this study, we examined the temporal relationship among blood pressure, endothelial dysfunction, and endothelial activation and the role of IKK in the rat model of androgen-driven 20-HETE-mediated hypertension. In Sprague-Dawley rats treated with 5α-dihydrotestosterone, renal vascular 20-HETE levels increased by day 2 of treatment from 17.7±2.4 to 57.7±9.7 ng/mg, whereas blood pressure elevation reached significance by day 3 (132.7±1.7 versus 117.2±0.8 mm Hg). In renal interlobar arteries, when compared with vehicle, 5α-dihydrotestosterone treatment increased the sensitivity to phenylephrine-induced vasoconstriction by 3.5-fold, decreased acetylcholine-induced vasorelaxation, and increased nuclear factor κB activity, all of which were attenuated by treatment with the 20-HETE antagonist, 20 hydroxyeicosa-6(Z),15(Z)-dienoic acid, (20-6,15-HEDE). Cotreatment with parthenolide, an IKK inhibitor, attenuated the androgen-dependent 20-HETE-mediated elevation in blood pressure (from 133.7±3.1 to 109.8±3.0 mm Hg). In addition, parthenolide treatment negated 20-HETE-mediated inhibition of the relaxing response to acetylcholine and 20-HETE-mediated increase in vascular nuclear factor κB activity. These findings suggest that inhibition of IKK attenuates the androgen-dependent 20-HETE-mediated increase in blood pressure by inhibiting both 20-HETE-dependent endothelial activation and dysfunction.

Original languageEnglish (US)
Pages (from-to)788-794
Number of pages7
JournalHypertension
Volume57
Issue number4
DOIs
Publication statusPublished - Apr 2011

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Keywords

  • 20-HETE
  • androgen
  • cytochrome P450
  • IKK
  • NF-κB

ASJC Scopus subject areas

  • Internal Medicine

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