Endothelial Cell-Specific NF-κB Inhibition Protects Mice from Atherosclerosis

Atherosclerosis is a progressive disorder of the arterial wall and the underlying cause of cardiovascular diseases such as heart attack and stroke. Today, atherosclerosis is recognized as a complex disease with a strong inflammatory component. The nuclear factor-kappa B (NF-kappa B) signaling pathway regulates inflammatory responses and has been implicated in atherosclerosis. Here, we addressed the function of NF-kappa B signaling in vascular endothelial cells in the pathogenesis of atherosclerosis in vivo. Endotheliumrestricted inhibition of NF-kappa B activation, achieved by ablation of NEMO/IKK gamma or expression of dominant-negative l kappa B alpha specifically in endothelial cells, resulted in strongly reduced atherosclerotic plaque formation in ApoE(-/-) mice fed with a cholesterol-rich diet. Inhibition of NF-kappa B abrogated adhesion molecule induction in endothelial cells, impaired macrophage recruitment to atherosclerotic plaques, and reduced expression of cytokines and chemokines in the aorta. Thus, endothelial NF-kappa B signaling orchestrates proinflammatory gene expression at the arterial wall and promotes the pathogenesis of atherosclerosis.