Abstract 890: Feed-forward Signaling of TNF alpha and NFkappa B Produces Endothelial Dysfunction in Coronary Arterioles In Type Ii Diabetic Mice.
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Nuclear factor-κB (NFκB) signaling reportedly increases tumor necrosis factor-alpha (TNF expression), and the oxidative stress induced by TNF may then lead to further increase NFκB expression, i.e., a feed-forward interaction. Accordingly, we hypothesized that this feed-forward interaction between TNF and NFκB may amplify one another toward the evolution of vascular disease in diabetes. To test this hypothesis, we assessed the role of NFκB in endothelial dysfunction in Lepr db mice by evaluation of endothelial function of isolated coronary resistance vessels of m Lepr db (heterozygote, normal) and Lepr db (homozygote, diabetic) mice. Coronary arterioles (40 –100 μm) were isolated and pressurized (60 cmH2O) without flow. Although dilation of vessels to the endothelium-independent vasodilator, sodium nitroprusside (SNP) was not different between Lepr db and m Lepr db mice (n = 6), dilation to the endothelium-dependent agonist, acetycholine (ACh) was reduced (n = 5, P < 0.05). Electron Paramagnetic Resonance (EPR) results show that superoxide production was reduced by NFκB antagonist (MG-132), or anti-TNF in Lepr db mice suggesting that NFκB and TNF were contributing to elevated oxidative stress. MG-132 (1 μM, n = 4) antagonized the inhibitory effect of Lepr db mice on ACh-induced dilation vs. Lepr db without treatment, but did not affect dilation in m Lepr db mice. To better understand the basis for enhanced contributions of TNF and NFκB in diabetes, we used Western analysis to assess expression of major proteins involved in TNF-mediated signaling. Previous studies have provided compelling evidence that IKK beta plays an essential role in NFκB activation in response to TNF, whereas IKK alpha appears to play a lesser role; therefore, we examined the expression levels of IKK alpha and IKK beta mRNA and protein in Lepr db null for TNF. The protein concentration and mRNA expression level of IKK alpha were increased in Lepr db mice null for TNF (db TNF- /db TNF- ) mice. One intriguing finding of this study is that the roles of IKK alpha and IKK beta appear reversed in the inflammatory response in diabetic Lepr db mice. Furthermore, our results indicate that NFκB and TNF signaling interact to amplify the oxidative stress and induce endothelial dysfunction in type II diabetes.
