We hypothesized that the interaction between tumor necrosis factor-α (TNF-α)/nuclear factor-κB (NF-κB) 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, endotheliumdependent (ACh) and -independent (sodium nitroprusside) vasodilation of isolated, pressurized coronary arterioles from mLepr db (heterozygote, normal), Leprdb (homozygote, diabetic), and Leprdb mice null for TNF-α (dbTNF-/db TNF-) 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-κB 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 mLepr db mice were unaffected. The protein expression of IKK-α and IKK-β were higher in Leprdb than in mLeprdb mice; the expression of IKK-β, but not the expression of IKK-α, was attenuated by MG-132, the antioxidant apocynin, or the genetic deletion of TNF-α in diabetic mice. Leprdb mice showed an increased insulin resistance, but NaSal improved insulin sensitivity. The protein expression of TNF-α and NF-κB and the protein modification of phosphorylated (p)-IKK-β and p-JNK were greater in Leprdb mice, but NaSal attenuated TNF-α, NF-κB, 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-α reduced superoxide production in Leprdb mice. In conclusion, our results indicate that the interaction between NF-κB and TNF-α signaling induces the activation of IKK-β and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes.
|American Journal of Physiology - Heart and Circulatory Physiology
|Published - Jun 2009
- Coronary microcirculation
- Nitric oxide
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)