Abstract 755: Adoptive Transfer of RAGE-Deficient T lymphocytes Attenuates Atherosclerosis in Diabetic Apolipoprotein E Null Mice
Atherosclerosis is an inflammatory disease, associated with immune responses and other metabolic factors such as diabetes. Receptor for advanced glycation end products (RAGE) plays a central role in diabetic atherosclerosis. However, the impact of immune cell RAGE on lesion development in atherosclerosis-prone mice has not yet been studied. Here, we tested the hypothesis that T lymphocyte RAGE contributed to lesion progression in established atherosclerosis in diabetic Apolipoprotein E (apoE) null mice.
Methods and Results: Male apoE null mice, apoE null/RAGE null (all in the C57BL/6 background) age 6 weeks, were rendered diabetic with streptozotocin; at 14 weeks of age, mice were sacrificed and aortas were collected for lesion analysis. The aortic mean lesion area in apoE null/RAGE null mice was 2.3-fold lower compared to that in apoE null mice, 61,120.87±4,258.86 μm2 (n=6) verus142,367.02 ±7,621.08 μμ2 (n=6), respectively, p<0.05. Moreover, the double knockout mice displayed no complex lesions compared to apoE null mice. To specifically dissect the role of T lymphocyte RAGE in the development of atherosclerosis in diabetes; we performed adoptive T cell transfer in diabetic apoE null mice. Briefly, CD4 and CD8 positive T cells were purified from apoE null mice and apoE null/RAGE null mice were then transferred into sublethally irridated diabetic apoE null mice at age 8 weeks, the chimeric mice were sacrificed at age 18 weeks. Quantitative morphometric analysis showed that mice receiving CD4+/CD8+ T cells from apoE null/RAGE null mice displayed a 6-fold reduction in mean lesion area, compared with apoE null mice receiving T cells from apoE null RAGE-expressing mice, 50,039.00±9,435.43 μm2 (n=7) verus 304,275.20±76,797.69 μm2 (n=6), p<0.01. Notably, serum levels of glucose, cholesterol and triglyceride did not differ between diabetic apoE null mice receving apoE null RAGE-expressing or deficient T cells, p>0.05.
Conclusions: These data provide definitive evidence that RAGE contributes significantly to the acceleration of atherosclerosis in diabetes, and that T lymphocyte RAGE is critically involved in this process. Therefore, cell-specific targeting RAGE might be a potential therapeutic strategy for treating atherosclerosis in diabetes.