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1 U Missouri
2 Columbia University
* To whom correspondence should be addressed. E-mail: Zhangcu{at}missouri.edu.
We hypothesized that impaired NO-dependent dilation (endothelial dysfunction) in type II diabetes results, in part, from elevated production of superoxide induced by the interaction of AGE/RAGE and TNF
signaling. We assessed the role of AGE/RAGE and TNF signaling in endothelial dysfunction in type II 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 acetycholine (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, because this increase was attenuated by sRAGE or NF
B inhibitor MG132. Protein and mRNA expression of NAD(P)H oxidase subunits including NOX-2, p22phox and p40phox increased in diabetic compared to 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, oxidative stress and endothelial dysfunction in type II diabetes.
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