Angiotensin II, type 2 receptor is not involved in the angiotensin II-mediated pro-atherogenic process in ApoE^-/- mice

Objective: Angiotensin II (Ang II) accelerates atherogenesis in ApoE ^-/- mice via the angiotensin II, type 1 receptor (AT₁) while the type 2 receptor (AT₂) is suggested to counteract atherogenesis. To confirm and further explore this possibility, we studied the effect of AT₂ receptor antagonism on Ang II-accelerated atherosclerosis. Methods: ApoE^-/- mice were fed a standard or high cholesterol diet (1.25%) for 4 weeks. Mice on each diet were treated with either Ang II (0.5 μg/kg per min) or Ang II in combination with PD123319 (3 mg/kg per day). Plaque distribution was assessed by en face quantification of the thoracic aorta and in cross-sections of the aortic root. Mean arterial pressure (MAP) was measured. AT₁ and AT₂ receptor expression were analysed using real-time polymerase chain reaction (PCR) and the localization of the AT₂ receptor protein confirmed with immunohistochemistry. Results: Ang II infusion increased MAP only in mice on a standard diet (P < 0.001). Regardless of diet, Ang II-infused mice had 22-30 times increased plaque area in the thoracic aorta (P < 0.001 for both). Ang II had no effect on plaque in the aortic root. Plaque area was not affected by PD123319. AT ₂ receptor was heavily expressed in the plaques and increased six- to ninefold by a high cholesterol diet and Ang II infusion (P < 0.01). Conclusion: Ang II increases the extent of atherosclerosis in ApoE^-/- mice. Despite up-regulation of the AT₂ receptor, we found no support for an effect of the AT₂ receptor on atherogenesis in this model.