Blockade of the NF-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Lifespans
Background—Nuclear factor-kappa B (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 genetically-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased, while blood flow and mitochondrial contents 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 lifespan. These anti-aging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity and aortic up-regulations of mitochondrial sirtuin-related proteins.
Conclusions—The endothelium plays important roles in obesity- and age-related disorders through intracellular NF-κB signaling, thereby, ultimately, impacting lifespan. Endothelial NF-κB signaling is a potential target for treating the metabolic syndrome as well as for anti-aging strategies.
- Received July 15, 2011.
- Accepted December 27, 2011.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited