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Brain Cytosolic Phospholipase A2? Mediates Angiotensin II-Induced Hypertension and Reactive Oxygen Species Production in Male Mice.

ABSTRACT: BACKGROUND:Recently, we reported that angiotensin II (Ang II)-induced hypertension is mediated by group IV cytosolic phospholipase A2? (cPLA2?) via production of prohypertensive eicosanoids. Since Ang II increases blood pressure (BP) via its action in the subfornical organ (SFO), it led us to investigate the expression and possible contribution of cPLA2? to oxidative stress and development of hypertension in this brain area. METHODS:Adenovirus (Ad)-green fluorescence protein (GFP) cPLA2? short hairpin (sh) RNA (Ad-cPLA2? shRNA) and its control Ad-scrambled shRNA (Ad-Scr shRNA) or Ad-enhanced cyan fluorescence protein cPLA2? DNA (Ad-cPLA2? DNA) and its control Ad-GFP DNA were transduced into SFO of cPLA2?+/+ and cPLA2?-/- male mice, respectively. Ang II (700 ng/kg/min) was infused for 14 days in these mice, and BP was measured by tail-cuff and radio telemetry. cPLA2 activity, reactive oxygen species production, and endoplasmic reticulum stress were measured in the SFO. RESULTS:Transduction of SFO with Ad-cPLA2? shRNA, but not Ad-Scr shRNA in cPLA2?+/+ mice, minimized expression of cPLA2?, Ang II-induced cPLA2? activity and oxidative stress in the SFO, BP, and cardiac and renal fibrosis. In contrast, Ad-cPLA2? DNA, but not its control Ad-GFP DNA in cPLA2?-/- mice, restored the expression of cPLA2?, and Ang II-induced increase in cPLA2 activity and oxidative stress in the SFO, BP, cardiac, and renal fibrosis. CONCLUSIONS:These data suggest that cPLA2? in the SFO is crucial in mediating Ang II-induced hypertension and associated pathogenesis. Therefore, development of selective cPLA2? inhibitors could be useful in treating hypertension and its pathogenesis.

SUBMITTER: Song CY

PROVIDER: S-EPMC5905655 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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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.

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Brain Cytosolic Phospholipase A2? Mediates Angiotensin II-Induced Hypertension and Reactive Oxygen Species Production in Male Mice.

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