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

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Publisher: American Physiological Society
Document Type: Author abstract; Report
Length: 287 words

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Abstract :

We hypothesized that the interaction between tumor necrosis factor-[alpha] (TNF-[alpha])/nuclear factor-[kappa]B (NF-[kappa]B) 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.sup.db] (heterozygote, normal), [Lepr.sup.db] (homozygote, diabetic), and [Lepr.sup.db] mice null for TNF-[alpha] ([db.sup.TNF-]/[db.sup.TNF-]) were examined. Although the dilation of vessels to sodium nitroprusside was not different between [Lepr.sup.db] and [mLepr.sup.db] mice, the dilation to ACh was reduced in [Lepr.sup.db] mice. The NF-[kappa]B antagonist MG-132 or the IKK-[beta] inhibitor sodium salicylate (NaSal) partially restored nitric oxide-mediated endothelium-dependent coronary arteriolar dilation in [Lepr.sup.db] mice, but the responses in [mLepr.sup.db] mice were unaffected. The protein expression of IKK-[alpha] and IKK-[beta] were higher in [Lepr.sup.db] than in [mLepr.sup.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.sup.db] mice showed an increased insulin resistance, but NaSal improved insulin sensitivity. The protein expression of TNF-[alpha] and NF-[kappa]B and the protein modification of phosphorylated (p)-IKK-[beta] and p-JNK were greater in [Lepr.sup.db] mice, but NaSal attenuated TNF-[alpha], NF-[kappa]B, p-IKK-[beta], and p-JNK in [Lepr.sup.db] mice. The ratio of p-insulin receptor substrate (IRS)-1 at Set307 to IRS-1 was elevated in [Lepr.sup.db] compared with [mLepr.sup.db] mice; both NaSal and the JNK inhibitor SP-600125 reduced the p-IRS-I-to-IRS-1 ratio in [Lepr.sup.db] mice. MG-132 or the neutralization of TNF-[alpha] reduced superoxide production in [Lepr.sup.db] mice. In conclusion, our results indicate that the interaction between NF-[kappa]B and TNF-[alpha] signaling induces the activation of IKK-[beta] and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes. coronary microcirculation; cytokines; inflammation; nitric oxide; vasodilation

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Gale Document Number: GALE|A202437565