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6β-hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II-induced hypertension and its pathogenesis in male mice.

Abstract
Previously, we showed that Cyp1b1 gene disruption minimizes angiotensin II-induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II-induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, in Cyp1b1(+/+) mice without altering Cyp1b1 gene expression; these effects of angiotensin II were not observed in Cyp1b1(-/-) mice. Angiotensin II-induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, and restored by treatment with 6β-hydroxytestoterone. In Cyp1b1(+/+) mice, 6β-hydroxytestosterone did not alter the angiotensin II-induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1b1(+/+) or in Cyp1b1(-/-) mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin-angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.
AuthorsAjeeth K Pingili, Mehmet Kara, Nayaab S Khan, Anne M Estes, Zongtao Lin, Wei Li, Frank J Gonzalez, Kafait U Malik
JournalHypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 65 Issue 6 Pg. 1279-87 (Jun 2015) ISSN: 1524-4563 [Electronic] United States
PMID25870196 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2015 American Heart Association, Inc.
Chemical References
  • Hydroxytestosterones
  • Reactive Oxygen Species
  • Angiotensin II
  • 6 beta-hydroxytestosterone
  • Cyp1b1 protein, mouse
  • Cytochrome P-450 CYP1B1
Topics
  • Angiotensin II (pharmacology)
  • Animals
  • Cardiomegaly (physiopathology)
  • Castration
  • Cytochrome P-450 CYP1B1 (genetics)
  • Disease Models, Animal
  • Gene Expression Regulation
  • Hydroxytestosterones (metabolism, pharmacology)
  • Hypertension (drug therapy, physiopathology)
  • Male
  • Mice
  • Random Allocation
  • Reactive Oxygen Species (metabolism)
  • Reference Values

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