Abstract 11999: Role of AGE/RAGE in Activating Dendritic Cells in Endothelial Dysfunction in Type 2 Diabetic Mice
We have previously found interactions among TNF, the receptor for advanced glycation end products (AGE), and RAGE in mediating endothelial oxidative stress. RAGE putatively functions as a stimulatory molecule to activate Dendritic cells (DCs) in coronary arterioles in diabetes. Thus, we hypothesized that AGE/RAGE signaling contributes to activation of vascular DCs in type 2 diabetic db/db mice. To test this, we examined the coronary arteriolar endothelial function, the expression of DCS in the coronary arterioles of control mice (Db/db) and diabetic mice (db/db) at 12-16 weeks of age. CD11c staining was elevated in db/db mice heart tissue but attenuated in db/db cross with DC deficient (CD11c-DTR) mice. Diabetic db/db mice yielded a high percentage (40 %) of CD11c positive staining in the vessels, but a lower percentage (2%) of CD11c positive staining was presented in db/db cross with CD11c-DTR mice, and another lower percentage (5%) was in db/db mice treated with soluble RAGE (sRAGE to antagonize RAGE signaling; 80 µg/mouse/day, i.p. for 10 days), which are comparable to that in lean control Db/db mice (10 %). Under the treatment with sRAGE in db/db mice, DC activation is attenuated, endothelium-dependent vasodilatory responses are greater, and inflammatory cytokines expression in coronary arterioles are attenuated vs. db/db mice. This provides some associative evidence that type 2 diabetes activates DCs, but that the model with no DCs_CD11c-DTR_does not show activation. mRNA expression of DCs was elevated in coronary arterioles in diabetic db/db mice. Protein expression of CD11c was elevated in db/db compared with Db/db controls, and db/db null for TNF (dbTNF-/dbTNF-) mice showed slightly reduced (but not statistically significant) CD11c expression. sRAGE treatment reduced CD11c expression in db/db mice, indicating AGE/RAGE acts up stream and TNF acts down stream from the dentric cells in the pathway. In conclusion, our data indicate that AGE/RAGE plays a key role in activating DCs, and that leads to the production of inflammatory cytokines (IFN and TNF), which cause the progression of inflammatory disorders initiating the spiral of endothelial dysfunction that occurs in coronary microcirculation in type 2 diabetes.
- © 2011 by American Heart Association, Inc.