Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans

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.)