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Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans
Yutaka Hasegawa, MD, PhD*; Tokuo Saito, MD, PhD*; Takehide Ogihara, MD, PhD; Yasushi Ishigaki, MD, PhD; Tetsuya Yamada, MD, PhD; Junta Imai, MD, PhD; Kenji Uno, MD, PhD; Junhong Gao, MD, PhD; Keizo Kaneko, MD, PhD; Tatsuo Shimosawa, MD, PhD; Tomoichiro Asano, MD, PhD; Toshiro Fujita, MD, PhD; Yoshitomo Oka, MD, PhD; Hideki Katagiri, MD, PhD
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.
