PS 16-05 ANGIOTENSIN II-INDUCED HYPERTENSION IS DEPENDENT ON THE BRAIN CYTOSOLIC PHOSPHOLIPASE A2Aα-GENERATED OXIDATIVE STRESS

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Abstract

Objective:

Angiotensin (Ang) II by activating cytosolic phospholipase A2a (cPLA2a) releases arachidonic acid (AA), and the pro-hypertensive AA metabolites mediate Ang II-induced hypertension and associated pathogenesis. These findings and the demonstration that Ang II increases blood pressure via generation of oxidative stress in subfornical organ (SFO) in the brain, led us to hypothesize that these effects of Ang II are dependent on cPLA2a activation in SFO.

Design and method:

To test this hypothesis, we investigated the effect of Ang II infusion (700ng/kg/min, s.c.) for 14 days in wild type (cPLA2a+/+) and cPLA2a-/- mice transduced in SFO with enhanced cyan-fluorescence protein (Ad-ECFP)-cPLA2a DNA.

Results:

Ang II increased mean arterial pressure (MAP) measured by radio-telemetry in cPLA2a+/+ but not cPLA2a-/- mice (100 ± 2 to 161 ± 6 mmHg vs. 104 ± 3 to 112 ± 3 mmHg, respectively, P < 0.05). Ang II increased cPLA2 activity, measured by immunohistochemistry using anti-phospho-Ser505, in SFO of cPLA2a+/+ but not cPLA2a-/- mice. Ang II increased reactive oxygen species (ROS) production measured by dihydroethidium staining (5.09 ± 0.31 to 8.99 ± 0.33 AU, P < 0.05), in SFO of cPLA2a+/+ but not in cPLA2a-/- mice. Ad-ECFP-cPLA2a DNA (1x1012 pfu/0.5 μL) but not Ad-GFP DNA transduced in SFO of cPLA2a-/- mice, restored Ang II effect on MAP and ROS production (115 ± 4 to 149 ± 2 mmHg and 4.40 ± 0.31 to 7.66 ± 0.47 AU with Ad-ECFP-cPLA2a DNA vs. 109 ± 5 to 116 ± 4 mmHg, and 4.04 ± 0.35 to 4.56 ± 0.19 AU with Ad-GFP, respectively, P < 0.05). In contrast, Ad-cPLA2a shRNA, but not Ad-shRNA transduced in SFO of cPLA2a+/+ mice, inhibited cPLA2 expression and its activity, and abolished Ang II-induced increase in blood pressure.

Conclusions:

These observations suggest that AA released by cPLA2a via one or more of its metabolites increase oxidative stress in SFO that promotes development of hypertension.

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