Abstract 229: A Critical Role of Group IV Cytosolic Phospholipase A2α in the Development of Ang II-induced Hypertension and Associated Cardiovascular Pathophysiology
This study was conducted to determine the contribution of Group IV cytosolic phospholipase A2α (cPLA2α) in the development of angiotensin (Ang) II-induced hypertension and associated pathophysiology. Eight week old male wild type (cPLA2α+/+) and cPLA2α knockout (cPLA2α-/-) mice were infused with Ang II (750 ng/kg/min) or its vehicle for 2 weeks and systolic blood pressure (SBP) was measured weekly by the tail cuff method. Ang II increased SBP in cPLA2α+/+ mice to a greater degree than in cPLA2α-/- mice (125 ± 2 to 186 ± 7 mmHg vs. 125 ± 2 to 132 ± 2 mmHg respectively, P < 0.05). The increase in SBP in Ang II infused cPLA2α+/+ mice was associated with cardiac hypertrophy, measured by heart to body weight ratio (5.0 ± 0.3 vehicle vs. 7.1 ± 0.4 Ang II, P < 0.05), which was reduced by 26.0 ± 3.9 % (P < 0.05) in cPLA2α-/- mice. Ang II caused cardiac fibrosis, as indicated by accumulation of intracardiac α-smooth muscle actin- and transforming growth factor-β-positive cells, and collagen deposition in cPLA2α+/+ but not cPLA2α-/- mice. Ang II infusion produced a maximal increase in the response of aortic rings to phenylephrine (2.5 ± 0.5 mN vehicle vs. 6.0 ± 0.7 mN Ang II, P < 0.05) and endothelin-1 (5.1 ± 1.0 mN vehicle vs. 9.5 ± 1.0 Ang II, P < 0.05), and caused endothelial dysfunction in cPLA2α+/+ mice as indicated by a decrease in maximal relaxation in response to acetylcholine (92.0 ± 2.3 % vehicle vs. 55.1 ± 5.7 % Ang II, P < 0.05), measured by wire myograph. The vascular responses to PE and ET-1 were attenuated by 21.5 ± 8.5 % and 22.9 ± 11.4 %, respectively, and the relaxation to ACh increased by 36.9 ± 7.7 % (P < 0.05) in Ang II treated cPLA2α-/- mice. Aortic production of reactive oxygen species (ROS), measured by 2-hydroxyethidium fluorescence, was increased in Ang II treated cPLA2α+/+ mice (25.3 ± 1.6 AU vehicle vs. 49.5 ± 3.9 AU Ang II, P < 0.05) but not cPLA2α-/- mice (22.7 ± 1.1 AU vehicle vs. 23.5 ± 1.2 AU Ang II, P < 0.05). These data suggest that cPLA2α contributes to Ang II-induced hypertension and associated cardiovascular pathophysiology, most likely due to release of arachidonic acid and activation of NADPH oxidase and generation of ROS. Thus, cPLA2α could serve as a potential therapeutic target in the treatment of hypertension and cardiac damage and vascular dysfunction associated with hypertension.
- © 2012 by American Heart Association, Inc.