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

Ajeeth Pingili, Mehmet Kara, Nayaab S. Khan, Anne M. Estes, Zongtao Lin, Wei Li, Frank J. Gonzalez, Kafait Malik

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1279-1287
Number of pages9
JournalHypertension
Volume65
Issue number6
DOIs
StatePublished - Jun 20 2015

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Hydroxytestosterones
Angiotensin II
Cytochrome P-450 Enzyme System
Testosterone
Hypertension
Blood Pressure
Angiotensin Type 1 Receptor
Castration
Angiotensins
Androgen Receptors
Cardiomegaly
Transforming Growth Factors
Peptidyl-Dipeptidase A
NADP
Renin
Smooth Muscle
Actins
Reactive Oxygen Species
Oxidoreductases
Fibrosis

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

6β-Hydroxytestosterone, a Cytochrome P450 1B1 Metabolite of Testosterone, Contributes to Angiotensin II-Induced Hypertension and Its Pathogenesis in Male Mice. / Pingili, Ajeeth; Kara, Mehmet; Khan, Nayaab S.; Estes, Anne M.; Lin, Zongtao; Li, Wei; Gonzalez, Frank J.; Malik, Kafait.

In: Hypertension, Vol. 65, No. 6, 20.06.2015, p. 1279-1287.

Research output: Contribution to journalArticle

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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.",
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AU - Gonzalez, Frank J.

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