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

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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

Fingerprint

Angiotensin II
Peptidyl-Dipeptidase A
Blood Pressure
Hypertension
Renin-Angiotensin System
Angiotensin Type 1 Receptor
Blood Vessels
Lisinopril
Angiotensinogen
Lentivirus
Enzyme Induction
Withholding Treatment
Angiotensin Receptors
Losartan
Eicosanoids
Microcirculation
Sprague Dawley Rats
cytochrome P-450 CYP4A2 (rat)
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Cultured Cells

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Sodhi, K., Wu, C. C., Cheng, J., Gotlinger, K., Inoue, K., Goli, M., ... 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

CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent. / Sodhi, Komal; Wu, Cheng Chia; Cheng, Jennifer; Gotlinger, Katherine; Inoue, Kazuyoshi; Goli, Mohan; Falck, J R; Abraham, Nader G.; Schwartzman, Michal L.

In: Hypertension, Vol. 56, No. 5, 11.2010, p. 871-878.

Research output: Contribution to journalArticle

Sodhi, K, Wu, CC, Cheng, J, Gotlinger, K, Inoue, K, Goli, M, Falck, JR, Abraham, NG & Schwartzman, ML 2010, 'CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent', Hypertension, vol. 56, no. 5, pp. 871-878. https://doi.org/10.1161/HYPERTENSIONAHA.110.154559
Sodhi, Komal ; Wu, Cheng Chia ; Cheng, Jennifer ; Gotlinger, Katherine ; Inoue, Kazuyoshi ; Goli, Mohan ; Falck, J R ; Abraham, Nader G. ; Schwartzman, Michal L. / CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent. In: Hypertension. 2010 ; Vol. 56, No. 5. pp. 871-878.
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