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

Abstract

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.