Abstract 508: AGE/RAGE Produces Endothelial Dysfunction in Coronary Arterioles in Type II Diabetic Mice
The interaction of advanced glycation end products (AGE) with its receptor (receptor for AGE [RAGE]) stimulates the production of superoxide. AGE/RAGE signaling in vascular tissue would increase oxidative stress and impair the bioavailability of NO. Accordingly, we hypothesized that impaired NO-dependent dilation (endothelial dysfunction) in type II diabetes results, in part, from elevated production of superoxide induced by AGE/RAGE signaling. To test this hypothesis, we assessed the role of AGE/RAGE signaling in endothelial dysfunction in type II diabetic (Leprdb) mice by evaluation of endothelial function of isolated coronary resistance vessels of m Leprdb (heterozygote, normal) and Leprdb (homozygote, diabetic) mice. Coronary arterioles (40 –100 μm) were isolated and pressurized (60 cmH2O) without flow. Although dilation of vessels to the endothelium-independent vasodilator, sodium nitroprusside (SNP) was not different between Leprdb and m Leprdb mice (n=6), dilation to the endothelium-dependent agonist, acetycholine (ACh) was reduced (10.56±1.4% [Leprdb] vs 46.12±4.58% [m Leprdb], n=5, P<0.05). Administration of a soluble form of RAGE (sRAGE, 50 μg/day, 7 days, i.p., n=4; to antagonize RAGE signaling) partially restored dilation in Leprdb mice (27.09±1.3%, P<0.05 vs Leprdb without treatment) but did not affect dilation in m Leprdb mice. Western blot analysis revealed elevations in RAGE in Leprdb mice and immunostaining indicated that the expression of RAGE in coronary arterioles was markedly increased in both endothelial and vascular smooth muscle in Leprdb vs m Leprdb mice. These results indicate that AGE/RAGE signaling plays a pivotal role in endothelial dysfunction in Type II diabetes.