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Am J Physiol Heart Circ Physiol. 2009 Jun;296(6):H1850-8. doi: 10.1152/ajpheart.01199.2008. Epub 2009 Apr 10.

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

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  • 1Michael E. DeBakey Institute, Texas A&M University, College Station, Texas, USA.


We hypothesized that the interaction between tumor necrosis factor-alpha (TNF-alpha)/nuclear factor-kappaB (NF-kappaB) via the activation of IKK-beta 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-alpha (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-kappaB antagonist MG-132 or the IKK-beta 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-alpha and IKK-beta were higher in Lepr(db) than in mLepr(db) mice; the expression of IKK-beta, but not the expression of IKK-alpha, was attenuated by MG-132, the antioxidant apocynin, or the genetic deletion of TNF-alpha in diabetic mice. Lepr(db) mice showed an increased insulin resistance, but NaSal improved insulin sensitivity. The protein expression of TNF-alpha and NF-kappaB and the protein modification of phosphorylated (p)-IKK-beta and p-JNK were greater in Lepr(db) mice, but NaSal attenuated TNF-alpha, NF-kappaB, p-IKK-beta, 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-alpha reduced superoxide production in Lepr(db) mice. In conclusion, our results indicate that the interaction between NF-kappaB and TNF-alpha signaling induces the activation of IKK-beta and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes.

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