Dataset Information

Testosterone Metabolite 6β-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Apoe^-/- Male Mice.

ABSTRACT: Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1-generated metabolite of testosterone, 6β-hydroxytestosterone (6β-OHT), contributes to Ang II-induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β-OHT to Ang II-induced AAA development in Apoe^-/- male mice. Methods and Results Intact or castrated Apoe^-/-/Cyp1b1^+/+ and Apoe^-/-/Cyp1b1^-/- male mice were infused with Ang II or its vehicle for 28 days, and administered 6β-OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II-infused Apoe^-/-/Cyp1b1^+/+ mice, compared with vehicle-treated mice, which were minimized in castrated Apoe^-/-/Cyp1b1^+/+ and intact Apoe^-/-/Cyp1b1^-/- mice infused with Ang II. Treatment with 6β-OHT significantly restored the incidence and severity of AAAs in Ang II-infused castrated Apoe^-/-/Cyp1b1^+/+ and intact Apoe^-/-/Cyp1b1^-/- mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II-infused intact Apoe^-/-/Cyp1b1^-/- mice. Conclusions Our results indicate that the testosterone-cytochrome P450 1B1-generated metabolite 6β-OHT contributes to Ang II-induced AAA development in Apoe^-/- male mice.

SUBMITTER: Mukherjee K

PROVIDER: S-EPMC8174379 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description: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.

Project description:Previously, we showed that peripheral administration of 6β-hydroxytestosterone, a CYP1B1 (cytochrome P450 1B1)-generated metabolite of testosterone, promotes angiotensin II-induced hypertension in male mice. However, the site of action and the underlying mechanism by which 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension is not known. Angiotensin II increases blood pressure by its central action, and CYP1B1 is expressed in the brain. This study was conducted to determine whether testosterone-CYP1B1 generated metabolite 6β-hydroxytestosterone locally in the brain promotes the effect of systemic angiotensin II to produce hypertension in male mice. Central CYP1B1 knockdown in wild-type (Cyp1b1+/+) mice by intracerebroventricular-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA attenuated, whereas reconstitution of CYP1B1 by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ in Cyp1b1-/- mice restored angiotensin II-induced increase in systolic blood pressure measured by tail-cuff. Intracerebroventricular-testosterone in orchidectomized (Orchi)-Cyp1b1+/+ but not in Orchi-Cyp1b1-/-, and intracerebroventricular-6β-hydroxytestosterone in the Orchi-Cyp1b1-/- mice restored the angiotensin II-induced: (1) increase in mean arterial pressure measured by radiotelemetry, and autonomic imbalance; (2) reactive oxygen species production in the subfornical organ and paraventricular nucleus; (3) activation of microglia and astrocyte, and neuroinflammation in the paraventricular nucleus. The effect of intracerebroventricular-6β-hydroxytestosterone to restore the angiotensin II-induced increase in mean arterial pressure and autonomic imbalance in Orchi-Cyp1b1-/- mice was inhibited by intracerebroventricular-small interfering (si)RNA-androgen receptor (AR) and GPRC6A (G protein-coupled receptor C6A). These data suggest that testosterone-CYP1B1-generated metabolite 6β-hydroxytestosterone, most likely in the paraventricular nucleus via AR and GPRC6A, contributes to angiotensin II-induced hypertension and neuroinflammation in male mice.

Project description:This study was conducted to test the hypothesis that the CYP1B1 (cytochrome P450 1B1)-testosterone metabolite 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension by promoting activation of group IV cPLA2α (cytosolic phospholipase A2α) and generation of prohypertensive eicosanoids in male mice. Eight-week-old male intact or orchidectomized cPLA2α+/+/Cyp1b1+/+ and cPLA2α-/-/Cyp1b1+/+ and intact cPLA2α+/+/Cyp1b1-/- mice were infused with angiotensin II (700 ng/kg/min, subcutaneous) for 2 weeks and injected with 6β-hydroxytestosterone (15 μg/g/every third day, intraperitoneal). Systolic blood pressure was measured by tail-cuff and confirmed by radiotelemetry. Angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production were reduced by disruption of the cPLA2α or Cyp1b1 genes or by administration of the arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid to cPLA2α+/+/Cyp1b1+/+ mice. 6β-hydroxytestosterone treatment restored these effects of angiotensin II in cPLA2α+/+/Cyp1b1-/- mice but not in orchidectomized cPLA2α-/-/Cyp1b1+/+ mice, which were lowered by 5,8,11,14-eicosatetraynoic acid in cPLA2α+/+/Cyp1b1-/- mice. Antagonists of prostaglandin E2-EP1/EP3 receptors and thromboxane A2-TP receptors decreased the effect of 6β-hydroxytestosterone in restoring the angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production in cPLA2α+/+/Cyp1b1-/- mice. These data suggest that 6β-hydroxytestosterone promotes angiotensin II-induced increase in systolic blood pressure and associated pathogenesis via cPLA2α activation and generation of eicosanoids, most likely prostaglandin E2 and thromboxane A2 that exerts prohypertensive effects by stimulating EP1/EP3 and TP receptors, respectively. Therefore, agents that selectively block these receptors could be useful in treating testosterone exacerbated angiotensin II-induced hypertension and its pathogenesis.

Dataset Information

Testosterone Metabolite 6β-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Apoe^-/- Male Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Testosterone Metabolite 6β-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Apoe-/- Male Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Testosterone Metabolite 6β-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Apoe^-/- Male Mice.