6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase A(2)α Activity

Singh, Purnima; Song, Chi Young; Dutta, Shubha R.; Pingili, Ajeeth; Shin, Ji Soo; Gonzalez, Frank J.; Bonventre, Joseph V.; Malik, Kafait U.

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 cPLA(2)α (cytosolic phospholipase A(2)α) and generation of prohypertensive eicosanoids in male mice. Eight-week-old male intact or orchidectomized cPLA(2)α(+/+)/Cyp1b1(+/+) and cPLA(2)α(–/–)/Cyp1b1(+/+) and intact cPLA(2)α(+/+)/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 cPLA(2)α or Cyp1b1 genes or by administration of the arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid to cPLA(2)α(+/+)/Cyp1b1(+/+) mice. 6β-hydroxytestosterone treatment restored these effects of angiotensin II in cPLA(2)α(+/+)/Cyp1b1(–/–) mice but not in orchidectomized cPLA(2)α(–/–)/Cyp1b1(+/+) mice, which were lowered by 5,8,11,14-eicosatetraynoic acid in cPLA(2)α(+/+)/Cyp1b1(–/–) mice. Antagonists of prostaglandin E(2)-EP1/EP3 receptors and thromboxane A(2)-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 cPLA(2)α(+/+)/Cyp1b1(–/–) mice. These data suggest that 6β-hydroxytestosterone promotes angiotensin II-induced increase in systolic blood pressure and associated pathogenesis via cPLA(2)α activation and generation of eicosanoids, most likely prostaglandin E(2) and thromboxane A(2) 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.