Abstract 10738: The Novel Role of Epsins in Atherosclerosis
Background: Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 and exhibit an abnormal vascular phenotype. We have recently published that endothelial epsins function as critical regulators of tumor angiogenesis by controlling the endocytosis of VEGFR2 (J Clin Invest. 2012). The goal of this project is to define the novel role of epsins in endothelial cells (EC) and macrophages in regulating inflammation-mediated atherosclerosis.
Methods and Results: To examine the role of endothelial and macrophage epsins in atherogenesis, we engineered mice with specific deletion of epsins in EC (EC-DKO) or myeloid cells (MΦ-DKO). Strikingly, these mice are viable but display markedly attenuated atherogenesis. Mice with either EC-DKO or MΦ-DKO on ApoE-/- background had a significant reduction in atherosclerotic lesion formation and macrophage infiltration compared to ApoE-/- mice fed a western diet. FACS analysis revealed that epsin deficiency greatly reduced TNFα and LPS-induced expression of adhesion molecules including ICAM-1, VCAM-1, P- and E-selectins, and CCR2 and MCP-1 in primary mouse aortic EC, and leukocyte recruitment in mouse aorta. Mechanistically, epsins promote TNFR/TLRs signaling and NF-κB and MAPK (JNK and p38) activation by enhancing recruitment of NEMO, an essential NF-kB activator. Conversely, in macrophages, epsin deficiency produces no change in LDL and scavenger receptor expression but impaired pinocytosis of Lucifer Yellow, indicative of a major defect in LDL lipid uptake. We also observed that a synthetic peptide comprising the epsin ubiquitin-interacting motif (UIM) and lesion homing sequence potently disrupts association of epsins with TNFR/TLR signaling complex in vitro, and inhibits atherosclerotic plaque in vivo. Our data show that epsins control atherosclerosis by promoting TNFR/TLR signaling in endothelial cells, facilitating LDL lipid uptake in macrophages, and provide a potential novel strategy to perturb atheroma progression.
Conclusion: Our results demonstrate a novel proatherogenic role of epsins in atherosclerosis by potentiating endothelium inflammation, augmenting leukocyte recruitment, and promoting foam cell formation.
- © 2013 by American Heart Association, Inc.