Key result
In male mice, 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis, likely acting as a permissive factor.
Why the study?
Does 6β-hydroxytestosterone contribute to angiotensin II-induced hypertension and cardiac pathogenesis in male mice?
Does 6β-hydroxytestosterone contribute to angiotensin II-induced hypertension and cardiac pathogenesis in male mice?
The testosterone metabolite 6β-hydroxytestosterone acts as a permissive factor in angiotensin II-induced hypertension and cardiac pathogenesis in male mice, suggesting CYP1B1 as a potential therapeutic target.
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.
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Pingili et al. (2015) studied Angiotensin II-induced hypertension. Angiotensin II infusion and 6β-hydroxytestosterone treatment vs. Cyp1b1(-/-) mice or castrated mice was evaluated on Systolic blood pressure and associated cardiac hypertrophy, fibrosis, and reactive oxygen species production. In male mice, 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis, likely acting as a permissive factor.
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