From Division of Molecular Metabolism and Diabetes (Y.H., T. Saito, Y.I., J.I., K.U., K.K., Y.O.) and Department of Metabolic Diseases, Center for Metabolic Diseases (T. Saito, T.O., T.Y., J.G., H.K.), Tohoku University Graduate School of Medicine, Sendai; Faculty of Medicine, Department of Clinical Laboratory (T. Shimosawa) and Department of Nephrology and Endocrinology, Faculty of Medicine (T.F.), University of Tokyo, Tokyo; and Department of Medical Science, Graduate School of Medicine, University of Hiroshima, Hiroshima (T.A.), Japan.
Correspondence to Hideki Katagiri, MD, PhD, Department of Metabolic Diseases, Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail katagiri@med.tohoku.ac.jp
↵* Drs Hasegawa and Saito contributed equally to this article.
Abstract
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Background—Nuclear factor-κB (NF-κB) 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-κB signaling in vivo, we generated transgenic mice expressing dominant-negative IκB under the Tie2 promoter/enhancer (E-DNIκB mice). These mice exhibited functional inhibition of NF-κB signaling specifically in endothelial cells. Although E-DNIκB 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-DNIκB mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-κB 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-κB signaling, thereby ultimately affecting life span. Endothelial NF-κB signaling is a potential target for treating the metabolic syndrome and for antiaging strategies.
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