Upregulation of Angiotensin II Type 2 Receptor (agtr2) Attenuates Atherosclerotic Lesion Formation and Enhances Apoptosis in the LDL Receptor Knockout Mice Fed High Cholesterol Diet

Abstract

Angiotensin II type 1 receptor (AT1R) exerts growth-promoting and anti-apoptotic effects, which contribute to atherogenesis. In contrast, type 2 receptor (AT2R) activation exerts anti-growth and pro-apoptotic effects. We tested the hypothesis that over-expression of AT2R will attenuate formation of atherosclerotic lesions. Low-density lipoprotein receptor knockout (LDLR KO) mice were injected via tail vein with recombinant AAV carrying AT2R (agtr2) cDNA (AAV/AT2R), AAV/Neo, or saline, and then put on a high cholesterol diet. At 18 weeks, all animals were sacrificed, and the aortas were harvested for AT2R expression and determination of atherosclerotic lesion formation. AT2R was highly expressed in mice given AAV/AT2R, but not in other groups. Atherosclerotic lesion formation and thickness of intima were significantly reduced in the LDRL KO mice with AT2R over-expression compared to other LDLR KO mice. Concurrently, there was suppression of oxidative stress (NADPH oxidase p67^phox and the transcription factor NF-κB) and increase in the free radical scavenger superoxide dismutase activity. Importantly, there was a marked increase in apoptosis in the atheromatous tissues in the LDLR KO mice with over-expression of AT2R. Thus, upregulation of AT2R by gene delivery in the LDLR KO mice reduces oxidative stress and increases apoptosis resulting in a reduction in atherosclerotic lesion formation.