Brain Cytosolic Phospholipase A(2)α Mediates Angiotensin II-Induced Hypertension and Reactive Oxygen Species Production in Male Mice

BACKGROUND: Recently, we reported that angiotensin II (Ang II)-induced hypertension is mediated by group IV cytosolic phospholipase A(2)α (cPLA(2)α) 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 cPLA(2)α to oxidative stress and development of hypertension in this brain area. METHODS: Adenovirus (Ad)-green fluorescence protein (GFP) cPLA(2)α short hairpin (sh) RNA (Ad-cPLA(2)α shRNA) and its control Ad-scrambled shRNA (Ad-Scr shRNA) or Ad-enhanced cyan fluorescence protein cPLA(2)α DNA (Ad-cPLA(2)α DNA) and its control Ad-GFP DNA were transduced into SFO of cPLA(2)α(+/+) and cPLA(2)α(−/−) 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. cPLA(2) activity, reactive oxygen species production, and endoplasmic reticulum stress were measured in the SFO. RESULTS: Transduction of SFO with Ad-cPLA(2)α shRNA, but not Ad-Scr shRNA in cPLA(2)α(+/+) mice, minimized expression of cPLA(2)α, Ang II-induced cPLA(2)α activity and oxidative stress in the SFO, BP, and cardiac and renal fibrosis. In contrast, Ad-cPLA(2)α DNA, but not its control Ad-GFP DNA in cPLA(2)α(−/−) mice, restored the expression of cPLA(2)α, and Ang II-induced increase in cPLA(2) activity and oxidative stress in the SFO, BP, cardiac, and renal fibrosis. CONCLUSIONS: These data suggest that cPLA(2)α in the SFO is crucial in mediating Ang II-induced hypertension and associated pathogenesis. Therefore, development of selective cPLA(2)α inhibitors could be useful in treating hypertension and its pathogenesis.