Molecular Cardiology Blockade of the Nuclear Factor- B Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans

Background—Nuclear factor-␬B (NF-␬B) 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-␬B signaling in vivo, we generated transgenic mice expressing dominant-negative I␬B under the Tie2 promoter/enhancer (E-DNI␬B mice). These mice exhibited functional inhibition of NF-␬B signaling specifically in endothelial cells. Although E-DNI␬B 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-DNI␬B mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-␬B 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-␬B signaling, thereby ultimately affecting life span. Endothelial NF-␬B signaling is a potential target for treating the metabolic syndrome and for antiaging strategies. N uclear factor-kappa B (NF-␬B) is a transcription factor regulating the gene expression of numerous cytokines, growth factors, adhesion molecules, and enzymes involved in a variety of pivotal cellular processes, including responses to inflammation and oxidative stress. 1 Without inflammatory stimuli, NF-␬B is maintained in the cytoplasm in a nonacti-vated form by association with an inhibitor subunit, I␬B. In response to activating stimuli, including tumor necrosis factor-␣ (TNF-␣), lipopolysaccharide, and other inflamma-tory cytokines, I␬B is phosphorylated by I␬B kinase ␤, resulting in proteolysis of I␬B. Consequently, a nuclear recognition site of NF-␬B is exposed, and NF-␬B is stimulated to move into the nucleus, resulting in mRNA expression of target genes, including inflammatory cytokines and adhesion molecules. 2 Obesity is characterized by a state of chronic low-grade inflammation. 3 Oxidative stress is also widely recognized as being associated with various obesity-related disorders. 4 Insulin resistance is an important mechanism underlying obesity-related disorders, eg, diabetes mellitus, hyperlipid-emia, and hypertension, collectively called the metabolic syndrome. 5,6 In these metabolic states, NF-␬B has been implicated in the processes of both inflammatory responses and oxidative stress. 7 Indeed, blockade of the NF-␬B signal-ing pathway by systemic administration of high-dose salicy-late or global disruption of I␬B kinase …