6β-Hydroxytestosterone, a Cytochrome P450 1B1 Metabolite of Testosterone, Contributes to Angiotensin II–Induced Hypertension and Its Pathogenesis in Male Mice. Issue 6 (June 2015)

• Record Type: Journal Article
• Authors: Pingili, Ajeeth K.; Kara, Mehmet; Khan, Nayaab S.; Estes, Anne M.; Lin, Zongtao; Li, Wei; Gonzalez, Frank J.; Malik, Kafait U.
• Is Part Of: Hypertension. Volume 65:Issue 6(2015:Jun.)
• Publication Date: 2015-06
• Subjects: Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.115.05396
• Languages: English
• ISSNs: 0194-911X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p>Previously, we showed that <italic>Cyp1b1</italic> 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 <italic>Cyp1b1</italic><sup>+/+</sup> mice without altering <italic>Cyp1b1</italic> gene expression; these effects of angiotensin II were not observed in <italic>Cyp1b1</italic><sup>−/−</sup> 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 <italic>Cyp1b1</italic><sup>−/−</sup> or castrated <italic>Cyp1b1</italic><sup>+/+</sup> mice, and restored by treatment with 6β-hydroxytestoterone. In <italic>Cyp1b1</italic><sup>+/+</sup> 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 <italic>Cyp1b1</italic><sup>+/+</sup> or in <italic>Cyp1b1</italic><sup>−/−</sup> 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.</p> </sec> </abstract>