Abstract 399: Deficiency of Angiotensin Type 1a Receptors in Adipocytes Increases Fat Mass in Angiotensin II-Infused LDLR-Deficient Mice but Has No Effect on Vascular Pathologies

Abstract

Objectives: Angiotensin II (AngII) promotes atherosclerosis and abdominal aortic aneurysms (AAA) through the angiotensin type 1a receptor (AT1aR). However, the cell type mediating these effects has not been defined. Adipose tissue surrounding the aorta may influence the inflammatory milieu within the vessel wall and thus contribute to disease progression. The purpose of this study was to determine the effect of adipocyte-AT1aR deficiency on development of AngII and diet-induced vascular pathologies in low density lipoprotein receptor deficient (LDLR-/-) mice. Methods and results: LDLR -/- mice with adipocyte-AT1aR deficiency (AT1aRaP2, n = 21) and littermates (AT1aRfl/fl, n=17) were fed a high-fat diet (HF, 42% kcal fat; 0.15 cholesterol) for 1 week prior to, and throughout, 28 days of AngII infusion (1,000 ng/kg/min). Adipocyte-AT1aR deficiency had no effect on AAA incidence (external diameter of aorta; AT1aRfl/fl 1.4±0.1 vs. AT1aRaP2 1.5±0.1 mm, p=0.41) and atherosclerotic lesion areas in the aortic arch (AT1aRfl/fl 7.1±0.8 vs. AT1aRaP2 8.3+0.8% lesion area, p=0.49). Serum cholesterol (AT1aRfl/fl 1981±109 vs. AT1aRaP2 2044±85 mg/dL, p=0.65) and triglyceride (AT1aRfl/fl 450±31 vs. AT1aRaP2 496±33 mg/dL, p=0.32) concentrations were also unaffected by adipocyte-AT1aR deficiency. Interestingly, body weight was significantly increased in AngII-infused AT1aRaP2 mice (AT1aRfl/fl 26.8±0.5 vs. AT1aRaP2 28.0±0.5 g, p=0.013 for interaction between genotype and time), due to increases in adipose mass (retroperitoneal fat; AT1aRfl/fl 0.26±0.03 vs. AT1aRaP2 0.36±0.02 g, p=0.017). Mice fed the HF diet for 3 months without AngII infusion did not exhibit any changes in atherosclerotic lesion area in the aortic arch (AT1aRfl/fl 14.3±1% vs. AT1aRaP2 11.7±1%, p=0.14). Conclusions: Adipocyte-AT1aR deficiency has no effect on development of diet- or AngII-induced atherosclerosis or AAAs in hypercholesterolemic mice. Interestingly, body weight and fat mass were increased in AngII-infused adipocyte AT1aR deficient mice. Future studies will elucidate the mechanisms through which AngII regulates body weight and fat mass under these conditions.