Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans
Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans
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DOI：
10.1161/circulationaha.111.054346
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发表时间：
2012-03-06
期刊：
影响因子：
37.8
通讯作者：
Katagiri, Hideki
中科院分区：
文献类型：
--
作者：
Hasegawa, Yutaka;Saito, Tokuo;Katagiri, Hideki
背景-核因子-κ B（NF-κ B）信号传导在生理和病理过程中起关键作用，例如对炎症和氧化应激的反应。方法和结果-为了检测内皮NF-κ B信号传导在体内的作用，我们产生了在Tie 2启动子/增强子下表达显性阴性I κ B的转基因小鼠（E-DNI κ B小鼠）。这些小鼠在内皮细胞中特异性地表现出NF-κ B信号传导的功能性抑制。虽然E-DNI κ B小鼠在年轻和消瘦时没有明显的表型变化，但它们受到保护，不发生与肥胖相关的胰岛素抵抗，无论是饮食诱导还是遗传诱导。E-DNI κ B小鼠中，肥胖诱导的巨噬细胞向脂肪组织的浸润和血浆氧化应激标志物减少，肌肉中的血流量和线粒体含量以及活跃期运动活动增加。除了抑制肥胖相关的代谢恶化外，阻断内皮NF-κ B信号传导可预防年龄相关的胰岛素抵抗和血管衰老，尤其是延长寿命。这些抗衰老表型也与氧化应激标志物减少，增加肌肉血流量，增强活动期运动活性，和主动脉上调线粒体sirtuin相关protein. Conclusions内皮细胞发挥重要作用，肥胖和年龄相关疾病，通过细胞内NF-κ B B信号，从而最终影响寿命。内皮NF-κ B信号转导是治疗代谢综合征和抗衰老策略的潜在靶点。（循环。2012;125：1122-1133）。
Background-Nuclear factor-kappa B (NF-kappa B) signaling plays critical roles in physiological and pathological processes such as responses to inflammation and oxidative stress.Methods and Results-To examine the role of endothelial NF-kappa B signaling in vivo, we generated transgenic mice expressing dominant-negative I kappa B under the Tie2 promoter/enhancer (E-DNI kappa B mice). These mice exhibited functional inhibition of NF-kappa B signaling specifically in endothelial cells. Although E-DNI kappa B mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet-or genetics-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased and blood flow and mitochondrial content in muscle and active-phase locomotor activity were increased in E-DNI kappa B mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-kappa B signaling prevented age-related insulin resistance and vascular senescence and, notably, prolonged life span. These antiaging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity, and aortic upregulation of mitochondrial sirtuin-related proteins.Conclusions-The endothelium plays important roles in obesity-and age-related disorders through intracellular NF-kappa B signaling, thereby ultimately affecting life span. Endothelial NF-kappa B signaling is a potential target for treating the metabolic syndrome and for antiaging strategies. (Circulation. 2012;125:1122-1133.)