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6β‐Hydroxytestosterone, a Cytochrome P450 1B1 Metabolite of Testosterone, Contributes to Angiotensin II‐Induced Vascular Dysfunction in Male Mice
Author(s) -
Pingili Ajeeth K,
Jennings Brett L,
Malik Kafait U
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1011.16
Subject(s) - endocrinology , medicine , angiotensin ii , endothelial dysfunction , vasodilation , cyp1b1 , phenylephrine , chemistry , sodium nitroprusside , endothelin 1 , oxidative stress , nitric oxide , cytochrome p450 , biology , blood pressure , receptor , metabolism
Previously, we showed that 6β‐hydroxytestosterone (6β‐OHT), a cytochrome P450 1B1 (CYP1B1)‐derived metabolite of testosterone, contributes to the development of angiotensin II (Ang II)‐induced hypertension and renal dysfunction in male mice. Ang II‐induced hypertension is associated with vascular dysfunction. In the present study we determined the contribution of 6β‐OHT to Ang II action on vascular reactivity, endothelial dysfunction, hypertrophy and fibrosis. In Ang II‐treated Cyp1b1 +/+ mice, responses of the thoracic aorta to phenylephrine (PE) and endothelin‐1 (ET‐1), media to lumen ratio were significantly increased compared to Ang II‐treated Cyp1b1 −/− or castrated Cyp1b1 +/+ mice. Treatment of the later two groups of mice with 6β‐OHT restored the effect of Ang II to increase responses of the thoracic aorta to phenylephrine (PE) and endothelin‐1 (ET‐1) and media to lumen ratio. Ang II infusion caused endothelial dysfunction, as indicated by decreased relaxation to acetylcholine (ACh) of the aorta from Cyp1b1 +/+ but not Cyp1b1 −/− or castrated Cyp1b1 +/+ mice. 6β‐OHT did not alter Ang II‐induced endothelial dysfunction in Cyp1b1 +/+ mice but resulted in endothelial dysfunction in Cyp1b1 −/− or castrated Cyp1b1 +/+ mice. Sodium nitroprusside(SNP)‐induced relaxation of the aorta was not altered in all the groups. Ang II infusion increased vascular fibrosis as indicated by increased α‐smooth muscle actin and collagen deposition, and reactive oxygen species production (ROS) as indicated by increased dihydroethidium (DHE) staining in Cyp1b1 +/+ as compared to Cyp1b1 −/− or castrated Cyp1b1 +/+ mice. 6β‐OHT did not alter Ang II‐induced fibrosis or oxidative stress in Cyp1b1 +/+ mice, however in Cyp1b1 −/− or castrated mice it restored these effects of Ang II. These data suggest that 6β‐OHT contributes to the development of hypertension, most likely via increased ROS generation and vascular reactivity and hypertrophy, and that CYP1B1 could serve as a novel target for the development of agents that mitigate hypertension and associated pathogenesis. Support or Funding Information This work was supported by the National Institutes of Health and National Heart, Lung, and Blood Institute grants R01HL‐19134–40 and R01HL‐079109‐09