Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans

Yutaka Hasegawa, Tokuo Saito, Takehide Ogihara, Yasushi Ishigaki, Tetsuya Yamada, Junta Imai, Kenji Uno, Junhong Gao, Keizo Kaneko, Tatsuo Shimosawa, Tomoichiro Asano, Toshiro Fujita, Yoshitomo Oka, Hideki Katagiri

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1122-1133
Number of pages12
JournalCirculation
Volume125
Issue number9
DOIs
Publication statusPublished - 2012 Mar 6

Keywords

  • NF-κB
  • inflammation
  • insulin resistance
  • oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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