Brain Cytosolic Phospholipase A2α 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)alpha (cPLA(2)alpha) 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)alpha to oxidative stress and development of hypertension in this brain area. METHODS Adenovirus (Ad)-green fluorescence protein (GFP) cPLA(2)alpha short hairpin (sh) RNA (Ad-cPLA(2)alpha shRNA) and its control Ad-scrambled shRNA (Ad-Scr shRNA) or Ad-enhanced cyan fluorescence protein cPLA(2)alpha DNA (Ad-cPLA(2)alpha DNA) and its control Ad-GFP DNA were transduced into SFO of cPLA(2)alpha(+/+) and cPLA(2)alpha(-/-) 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)alpha shRNA, but not Ad-Scr shRNA in cPLA(2)alpha(+/+) mice, minimized expression of cPLA(2)alpha, Ang II-induced cPLA(2)alpha activity and oxidative stress in the SFO, BP, and cardiac and renal fibrosis. In contrast, Ad-cPLA(2)alpha DNA, but not its control Ad-GFP DNA in cPLA(2)alpha(-/-) mice, restored the expression of cPLA(2)alpha, 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)alpha in the SFO is crucial in mediating Ang II-induced hypertension and associated pathogenesis. Therefore, development of selective cPLA(2)alpha inhibitors could be useful in treating hypertension and its pathogenesis.