TY - JOUR
T1 - Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans
AU - Hasegawa, Yutaka
AU - Saito, Tokuo
AU - Ogihara, Takehide
AU - Ishigaki, Yasushi
AU - Yamada, Tetsuya
AU - Imai, Junta
AU - Uno, Kenji
AU - Ko, Junhon
AU - Kaneko, Keizo
AU - Shimosawa, Tatsuo
AU - Asano, Tomoichiro
AU - Fujita, Toshiro
AU - Oka, Yoshitomo
AU - Katagiri, Hideki
PY - 2012/3/6
Y1 - 2012/3/6
N2 - 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.
AB - 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.
KW - NF-κB
KW - inflammation
KW - insulin resistance
KW - oxidative stress
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U2 - 10.1161/CIRCULATIONAHA.111.054346
DO - 10.1161/CIRCULATIONAHA.111.054346
M3 - Article
C2 - 22302838
AN - SCOPUS:84857914467
VL - 125
SP - 1122
EP - 1133
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 9
ER -