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.