Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension
| Autor: | Nancy J. Olsen, Fadi Adas, Mark A. Magnuson, Diane S. Keeney, Matthew D. Breyer, Michael R. Waterman, John R. Falck, Vijaykumar R. Holla, William J. Kovacs, Xueying Zhao, Edward Price, Jorge H. Capdevila, John D. Imig |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Blood Pressure Pharmacology Kidney urologic and male genital diseases Mixed Function Oxygenases Mice chemistry.chemical_compound Cytochrome P-450 Enzyme System Hydroxyeicosatetraenoic Acids Testosterone heterocyclic compounds Mice Knockout Sex Characteristics Arachidonic Acid Multidisciplinary Dihydrotestosterone Biological Sciences respiratory system 20-Hydroxyeicosatetraenoic acid Cardiovascular physiology medicine.anatomical_structure Enzyme Induction Hypertension Androgens Female Cytochrome P-450 CYP4A medicine.drug medicine.medical_specialty medicine.drug_class Biology Renal Circulation Microsomes Internal medicine medicine Animals Castration RNA Messenger Renal circulation organic chemicals Androgen enzymes and coenzymes (carbohydrates) Endocrinology Blood pressure chemistry Vascular Resistance Gene Deletion CYP4A11 |
| Zdroj: | Proceedings of the National Academy of Sciences. 98:5211-5216 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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