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AJP: Heart and Circulatory Physiology

Year: 2009  |  Volume: 296  |  Issue: 6  |  Page No.: 1850 - 1858

Feed-forward signaling of TNF-{alpha} and NF-{kappa}B via IKK-{beta} pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice

J Yang, Y Park, H Zhang, X Xu, G. A Laine, K. C Dellsperger and C. Zhang


We hypothesized that the interaction between tumor necrosis factor- (TNF-)/nuclear factor-B (NF-B) via the activation of IKK-β may amplify one another, resulting in the evolution of vascular disease and insulin resistance associated with diabetes. To test this hypothesis, endothelium-dependent (ACh) and -independent (sodium nitroprusside) vasodilation of isolated, pressurized coronary arterioles from mLeprdb (heterozygote, normal), Leprdb (homozygote, diabetic), and Leprdb mice null for TNF- (dbTNF–/dbTNF–) were examined. Although the dilation of vessels to sodium nitroprusside was not different between Leprdb and mLeprdb mice, the dilation to ACh was reduced in Leprdb mice. The NF-B antagonist MG-132 or the IKK-β inhibitor sodium salicylate (NaSal) partially restored nitric oxide-mediated endothelium-dependent coronary arteriolar dilation in Leprdb mice, but the responses in mLeprdb mice were unaffected. The protein expression of IKK- and IKK-β were higher in Leprdb than in mLeprdb mice; the expression of IKK-β, but not the expression of IKK-, was attenuated by MG-132, the antioxidant apocynin, or the genetic deletion of TNF- in diabetic mice. Leprdb mice showed an increased insulin resistance, but NaSal improved insulin sensitivity. The protein expression of TNF- and NF-B and the protein modification of phosphorylated (p)-IKK-β and p-JNK were greater in Leprdb mice, but NaSal attenuated TNF-, NF-B, p-IKK-β, and p-JNK in Leprdb mice. The ratio of p-insulin receptor substrate (IRS)-1 at Ser307 to IRS-1 was elevated in Leprdb compared with mLeprdb mice; both NaSal and the JNK inhibitor SP-600125 reduced the p-IRS-1-to-IRS-1 ratio in Leprdb mice. MG-132 or the neutralization of TNF- reduced superoxide production in Leprdb mice. In conclusion, our results indicate that the interaction between NF-B and TNF- signaling induces the activation of IKK-β and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes.

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