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Previously, we showed thatCyp1b1 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, inCyp1b1 +/+ mice without alteringCyp1b1 gene expression; these effects of angiotensin II were not observed inCyp1b1 −/− 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 inCyp1b1 −/− or castratedCyp1b1 +/+ mice, and restored by treatment with 6β-hydroxytestoterone. InCyp1b1 +/+ 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 inCyp1b1 +/+ or inCyp1b1 −/− 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.

hypertension

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