Marshall Digital Scholar

Title

CYP4A2-Induced Hypertension Is 20-Hydroxyeicosatetraenoic Acid– and Angiotensin II–Dependent

Authors

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

Document Type

Article

Publication Date

Fall 9-13-2010

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 (1103 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.

Comments

Copyright © 2010 American Heart Association, Inc. All rights reserved.

doi: 10.1161/HYPERTENSIONAHA.110.154559

Recommended Citation

Sodhi K, Wu CC, Cheng J, Gotlinger K, Inoue K, Goli M, Falck JR, Abraham NG, Schwartzman ML. CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid–and angiotensin II–dependent. Hypertension. 2010;56(5):871-8.