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

¹Michael E. DeBakey Institute, Texas A&M University, College Station, Texas; and ²Departments of Internal Medicine, and Medical Pharmacology and Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia Missouri

Submitted 16 November 2008 ; accepted in final form 26 March 2009

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 mLepr^db (heterozygote, normal), Lepr^db (homozygote, diabetic), and Lepr^db mice null for TNF- (db^TNF–/db^TNF–) were examined. Although the dilation of vessels to sodium nitroprusside was not different between Lepr^db and mLepr^db mice, the dilation to ACh was reduced in Lepr^db 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 Lepr^db mice, but the responses in mLepr^db mice were unaffected. The protein expression of IKK- and IKK-β were higher in Lepr^db than in mLepr^db 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. Lepr^db 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 Lepr^db mice, but NaSal attenuated TNF-, NF-B, p-IKK-β, and p-JNK in Lepr^db mice. The ratio of p-insulin receptor substrate (IRS)-1 at Ser307 to IRS-1 was elevated in Lepr^db compared with mLepr^db mice; both NaSal and the JNK inhibitor SP-600125 reduced the p-IRS-1-to-IRS-1 ratio in Lepr^db mice. MG-132 or the neutralization of TNF- reduced superoxide production in Lepr^db 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.

coronary microcirculation; cytokines; inflammation; nitric oxide; vasodilation

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