Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension

Vijaykumar R. Holla, Fadi Adas, John D. Imig, Xueying Zhao, Edward Price, Nancy Olsen, William J. Kovacs, Mark A. Magnuson, Diane S. Keeney, Matthew D. Breyer, John R. Falck, Michael R. Waterman, Jorge H. Capdevila

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

Hypertension is a leading cause of cardiovascular, cerebral, and renal disease morbidity and mortality. Here we show that disruption of the Cyp 4a14 gene causes hypertension, which is, like most human hypertension, more severe in males. Male Cyp 4a14 (-/-) mice show increases in plasma androgens, kidney Cyp 4a12 expression, and the formation of prohypertensive 20-hydroxyarachidonate. Castration normalizes the blood pressure of Cyp 4a14 (-/-) mice and minimizes Cyp 4a12 expression and arachidonate ω-hydroxylation. Androgen replacement restores hypertensive phenotype, Cyp 4a12 expression, and 20-hydroxy-arachidonate formation. We conclude that the androgen-mediated regulation of Cyp 4a arachidonate monooxygenases is an important component of the renal mechanisms that control systemic blood pressures. These results provide direct evidence for a role of Cyp 4a isoforms in cardiovascular physiology, establish Cyp 4a14 (-/-) mice as a monogenic model for the study of cause/effect relationships between blood pressure, sex hormones, and P450 ω-hydroxylases, and suggest the human CYP 4A homologues as candidate genes for the analysis of the genetic and molecular basis of human hypertension.

Original languageEnglish (US)
Pages (from-to)5211-5216
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number9
DOIs
StatePublished - Apr 24 2001

ASJC Scopus subject areas

  • General

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