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.
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.
Michael E. DeBakey Institute, Texas A&M University, College Station, Texas, USA.
Jiyeon
J
Yang
Yoonjung
Y
Park
Hanrui
H
Zhang
Xiangbin
X
Xu
Glen A
GA
Laine
Kevin C
KC
Dellsperger
Cuihua
C
Zhang
D000818:Animals; D030161:Avian Proteins / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003324:Coronary Artery Disease / Q000150:complications / Q000378:metabolism*; D003326:Coronary Circulation / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014657:Vasculitis / Q000150:complications / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
D030161:Avian Proteins; D001786:Blood Glucose; D020672:I-kappa B Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; C066541:LEP100 protein, Gallus gallus; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases