NF-KB, Inflammation and Vascular Remodeling

近年来越来越多的证据支持亚急性炎症在脑出血中的潜在作用 心血管疾病的发病机制以及胰岛素抵抗和2型糖尿病。这些疾病 它们本身在易感性方面是有联系的，这表明炎症可能形成了 致病的“共同土壤”。我们实验室最近发现炎症性IKKbetaNF-kappaB途径是一种 胰岛素抵抗的潜在特征。我们发现：(A)核因子-kappaB被肥胖和西方 脂肪和肝脏中的饮食，但不是肌肉中的饮食，(B)这会导致促炎细胞因子的产生(例如IL-6， 抵抗素、IL-1β、肿瘤坏死因子-α)和其他与高血压相关的炎症标志物和潜在介质 代谢综合征(如CRP、PAI-1等)，(C)在脂肪或肝脏中转基因激活核因子-kappaB可模拟这些 发生并导致全身性胰岛素抵抗，(D)胰岛素抵抗可通过移植传播 受影响的脂肪，(E)胰岛素抵抗可通过中和脂肪或肝脏中核因子-kappaB刺激的细胞因子而可逆， 以及(F)也许最重要的是，从遗传或药物上抑制IKKβ和NF-kappaB， 逆转动物和人类的胰岛素抵抗。这个应用程序建议测试肥胖-或者 西方饮食激活的核因子-kappaB类似地促进血管重构(即这是否代表 “共同土壤”)。特别提出的问题包括：(1)脂肪或肝脏是否存在亚急性“炎症”？ 肥胖或西方饮食诱导的水平，促进血管重塑？转基因FIKK和LIKK小鼠， 与易患动脉粥样硬化的LDLR-/-和/或APOE-/-小鼠杂交，将喂食致动脉粥样硬化的饮食和血管 损伤将被记分。(2)抑制核因子-kappaB和随之而来的炎症是否会在脂肪或肝脏中级联 保护老鼠免受动脉粥样硬化的侵袭？与Ldlr-/-和/或杂交的转基因FISR和LISR小鼠 APOE-/-老鼠将测试这些问题。(3)核因子-kappaB的靶标和活性调节剂A20表达上调 受西方饮食和肥胖的影响。此外，A20基因的多态赋予遗传易感性。 小鼠的动脉粥样硬化。我们将确定A20活性改变是否会影响胰岛素抵抗和 利用基因敲除和转基因小鼠技术进行血管重塑。(4)药物抑制 核因子-kappaB降低动脉粥样硬化风险？我们已经广泛使用水杨酸盐来抑制核因子-kappaB，逆转 胰岛素抵抗和治疗动物和人类的糖尿病。我们现在问的是，类似的养生法 降低血管病变形成的风险。这些研究测试了共享的“煽动性”是否 前置因素易导致胰岛素抵抗和动脉粥样硬化的发展，即 肥胖和膳食中脂肪和肝脏中的核因子-kappaB的激活代表了长期寻求的“共同土壤”的元素。

Increasing evidence over recent years supports potential roles for subacute inflammation in the pathogenesis of cardiovascular disease as well as insulin resistance and type 2 diabetes. These diseases are themselves linked in terms of predisposition, suggesting that inflammation may form the basis of a pathogenic "common soil." Our lab recently identified the inflammatory IKKbetaNF-kappaB pathway as an underlying feature of insulin resistance. We have found that (A) NF-kappaB is activated by obesity and Western diet in fat and liver, but not muscle, (B) this leads to the production of proinflammatory cytokines (e.g. IL-6, resistin, IL-1beta, TNF-alpha) and other markers and potential mediators of inflammation associated with the metabolic syndrome (e.g. CRP, PAI-1, etc.), (C) transgenic activation of NF-kappaB in fat or liver mimics these events and causes systemic insulin resistance, (D) insulin resistance is transmissible by transplanting affected fat, (E) insulin resistance is reversible by neutralizing cytokines stimulated by NF-kappaB in fat or liver, and (F), perhaps most importantly, inhibition of IKKbeta and NF-kappaB, either genetically or pharmacologically, reverses insulin resistance in animals and humans. This application proposes to test whether obesity- or Western diet-activated NF-kappaB similarly promotes vascular remodeling (i.e. whether this represents the "common soil"). Specifically asked questions include: (1) Does subacute "inflammation" in fat or liver, at levels induced by obesity or Western diet, promote vascular remodeling? Transgenic FIKK and LIKK mice, crossed with atherosclerosis-prone Ldlr-/- and/or Apoe-/- mice, will be fed atherogenic diets and vascular lesions will be scored. (2) Does inhibition of NF-kappaB and consequent inflammation cascades in fat or liver protect mice from developing atherosclerosis? Transgenic FISR and LISR mice crossed with Ldlr-/- and/or Apoe-/- mice will test these questions. (3) A20, a target of NF-kappaB and modulator of its activity, is upregulated by Western diet and obesity. Moreover, a polymorphism in A20 confers genetic susceptibility to atherosclerosis in mice. We will determine whether altered A20 activity influences insulin resistance and vascular remodeling using knock-out and transgenic mouse technologies. (4) Does pharmacologic inhibition of NF-kappaB decrease risk for atherosclerosis? We have used salicylates extensively to inhibit NF-kappaB, reverse insulin resistance and treat diabetes in animals and humans. We now ask whether similar regimens decrease risk for the formation of vascular lesions. These studies test whether shared 'inflammatory' antecedents predispose to the development of both insulin resistance and atherosclerosis, i.e. whether obesity and dietary activation of NF-kappaB in fat and liver represent elements of the long sought "common soil."