AGE/RAGE produces endothelial dysfunction in coronary arterioles in Type 2 diabetic mice

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Abstract
We hypothesized that impaired nitric oxide (NO)-dependent dilation (endothelial dysfunction) in Type 2 diabetes results, in part, from elevated production of superoxide (O2•−) induced by the interaction of advanced glycation end products (AGE)/receptor for AGE (RAGE) and TNF-α signaling. We assessed the role of AGE/RAGE and TNF-α signaling in endothelial dysfunction in Type 2 diabetic (Leprdb) mice by evaluation of endothelial function in isolated coronary resistance vessels of normal control (nondiabetic, m Leprdb) and diabetic mice. Although dilation of vessels to the endothelium-independent vasodilator sodium nitroprusside (SNP) was not different between diabetic and control mice, dilation to the endothelium-dependent agonist acetylcholine (ACh) was reduced in diabetic vs. control mice. The activation of RAGE with RAGE agonist S100b eliminated SNP-potentiated dilation to ACh in Leprdb mice. Administration of a soluble form of RAGE (sRAGE) partially restored dilation in diabetic mice but did not affect dilation in control mice. The expression of RAGE in coronary arterioles was markedly increased in diabetic vs. control mice. We also observed in diabetic mice that augmented RAGE signaling augmented expression of TNF-α, because this increase was attenuated by sRAGE or NF-κB inhibitor MG132. Protein and mRNA expression of NAD(P)H oxidase subunits including NOX-2, p22phox, and p40phox increased in diabetic compared with control mice. sRAGE significantly inhibited the expression of NAD(P)H oxidase in diabetic mice. These results indicate that AGE/RAGE signaling plays a pivotal role in regulating the production/expression of TNF-α, oxidative stress, and endothelial dysfunction in Type 2 diabetes.