Abstract 918: Roles of AT2 Receptor in Adipose Tissue Function and Differentiation in Atherosclerosis: Study with Gene-deficient Mice Treated with High Cholesterol Diet
Objective: Atherosclerosis is induced by various pathological changes, such as hypercholesterolemia, endothelial cell dysfunction, inflammation, and lipid accumulation. Renin-angiotensin system is widely known to be involved in these changes. However, the change in adipose tissue functions in atherogenesis is not yet totally clear. We have previously reported that AT1 receptor blockade in apolipoprotein E-deficient (ApoEKO) mice decreased adipocyte size and adipocyte differentiation in white adipose tissue. However, the roles of AT2 receptor in adipose tissues have not been well defined. In this study, we examined the possibilities that AT2 receptor stimulation could ameliorate adipocyte dysregulation in atherosclerotic ApoEKO mice, thereby contributing to the inhibition of atherosclerosis. Methods and Results: Male ApoEKO fed with normal diet mice at 6 months of age showed the enlargement of adipocyte size with 10-fold higher level of plasma cholesterol than wild type (C57BL/6) mice and marked atherosclerotic changes in proximal aorta. AT2 receptor mRNA levels were higher at 2 months of age and gradually decreased. Deletion of AT2 receptor in ApoEKO mice (AT2/ApoEKO) showed lower adipose weight until 4 months of age and did not significantly change body weight and epididymal adipose tissue weight at 6 months of age. In epididymal adipocyte in AT2/ApoEKO mice, expression of angiotensinogen and C/EBPδ, a transcription factor of adipocyte, was decreased at 2 months of age, but adiocyte size and the expression of adiponectin, PPARγ and C/EBPα were not significantly different from those in ApoEKO mice. Next, to exaggerate atherosclerotic changes, ApoEKO and AT2/ApoEKO mice were fed high-cholesterol diet (HCD: 1.25% cholesterol). Treatment with HCD further decreased the expression of PPARγ, C/EBPα and aP2 in epididymal adipose tissue of AT2/ApoEKO mice at early period of 2 weeks than that in ApoEKO mice and showed enlarged adipocyte size in AT2/ApoEKO mice at 10 weeks with enhanced atherosclerotic lesion and lipid deposition. Conclusion: These results suggest that AT2 receptor stimulation in adipose tissue is involved in adipocyte differentiation and adipocyte function at earlier stage, thereby contributing to prevention of atherogenesis.