CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent

Komal Sodhi, Cheng Chia Wu, Jennifer Cheng, Katherine Gotlinger, Kazuyoshi Inoue, Mohan Goli, J R Falck, Nader G. Abraham, Michal L. Schwartzman

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

We have shown previously that increased vascular endothelial expression of CYP4A2 leads to 20-hydroxyeicosatetraenoic (20-HETE)-dependent hypertension. The renin-angiotensin system is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and the renin-angiotensin system. In normotensive (110±3 mm Hg) Sprague-Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139±1, 145±3, and 150±2 mm Hg at 3, 5, and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163±3 mm Hg. Treatment with lisinopril, losartan, or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor and increased levels of plasma and tissue angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen, or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and angiotensin II type 1 receptor expression and increases angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of the renin-angiotensin system that is likely initiated at the level of ACE induction.

Original languageEnglish (US)
Pages (from-to)871-878
Number of pages8
JournalHypertension
Volume56
Issue number5
DOIs
StatePublished - Nov 2010

Keywords

  • 20-HETE
  • ACE
  • angiotensin II
  • cytochrome P450
  • hypertension

ASJC Scopus subject areas

  • Internal Medicine

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    Sodhi, K., Wu, C. C., Cheng, J., Gotlinger, K., Inoue, K., Goli, M., Falck, J. R., Abraham, N. G., & Schwartzman, M. L. (2010). CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent. Hypertension, 56(5), 871-878. https://doi.org/10.1161/HYPERTENSIONAHA.110.154559