6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase A2α Activity. Issue 4 (October 2021)

• Record Type: Journal Article
• Authors: Singh, Purnima; Song, Chi Young; Dutta, Shubha R.; Pingili, Ajeeth; Shin, Ji Soo; Gonzalez, Frank J.; Bonventre, Joseph V.; Malik, Kafait U.
• Is Part Of: Hypertension. Volume 78:Issue 4(2021)
• Publication Date: 2021-10
• Subjects: blood pressure -- hypertension -- mice -- tail -- testosterone; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.121.17927
• Languages: English
• ISSNs: 0194-911X

Abstract

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 cPLA2 α (cytosolic phospholipase A2 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 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 cPLA 2 α +/+ / Cyp1b1 –/– mice. These data suggest that 6β-hydroxytestosterone promotes angiotensin II-induced increase in systolic blood pressure and associated pathogenesis via cPLA2 α 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. Abstract : Supplemental Digital Content is available in the text.