Abstract 253: NOTCH1 Protects Against Atherosclerosis by Repressing Endothelial Activation and Recruitment of Inflammatory Cells
Maintenance of endothelial homeostasis is critical in the prevention of vascular disorders including atherosclerosis. While we have a good understanding of the mechanisms that promote endothelial activation, less understood are the mechanisms that counterbalance this state. We found that inducible deletion of Notch1 in the endothelium of adult mice led to the accumulation of CD45+ cells in the subendothelial space of large arteries. NOTCH1 is constitutively expressed in adult arteries of mouse and human in vivo but it is excluded from veins. Together these observations led us to speculate that NOTCH1 might actively suppress the acquisition of a pro-inflammatory state in adult endothelium of large arteries. In fact, knockdown of NOTCH1 in human aortic endothelial cells (HAECs) in vitro triggered the expression of inflammatory cytokines in the absence of any other stimuli. Furthermore exposure of HAECs to oxidized phospholipids (OxPAPC) resulted in a rapid reduction of the expression levels of NOTCH1 and several NOTCH1-target genes. Using gene expression microarrays, we found that approximately 25% of the genes differentially expressed after exposure to OxPAPC (by 20%) were similarly regulated (ie either proportionally down or upregulated) when NOTCH1 was knockdown in HAECs, suggesting that these two events might be linked. Among these genes, CXCL1, a molecule previously shown to facilitate monocyte recruitment and binding to the endothelium, was increased in both conditions. Upregulation of CXCL1 upon exposure to OxPAPC was also consistently observed in a cohort of cells isolated from 147 individual donors and suppression of NOTCH1 also led to increase of the chemokine at the mRNA and protein levels. These data indicated that constant NOTCH1 expression was required for a homeostatic anti-inflammatory phenotype in the endothelium. We conclude that NOTCH1 may provide inherent protection to the endothelium during the initial stages of atherosclerosis by repressing the recruitment of inflammatory cells. Thus, decline of endogenous endothelial NOTCH1 levels is likely to constitute a predisposing factor for atherosclerosis.
Author Disclosures: A. Briot: None. M. Civelek: None. A. Seki: None. S. Dry: None. M. Fishbein: None. A.J. Lusis: None. J. Berliner: None. L.M. Iruela-Arispe: None.
- © 2014 by American Heart Association, Inc.