Abstract
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 epsins function as 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) in regulating inflammation-mediated atherogenesis. Methods and results To examine the role of endothelial epsins in atherogenesis, we engineered mice with constitutive deletion of epsins in EC (EC-DKO). Strikingly, these mice are viable but display markedly attenuated atherogenesis on an ApoE null background in response to hypercholesterolemia. Oil red O staining revealed that ApoE-/- mice with endothelial deletion of epsins had a significant reduction in atherosclerotic lesion area in aortic root and macrophage infiltration compared to ApoE-/- mice after being fed a western diet for 10 weeks. FACS analysis revealed that deletion of epsins greatly reduced TNFα and LPS-induced expression of adhesion molecules (ICAM & VCAM), selectins (P- & E-), CCR2 and MCP-1 in primary mouse aortic EC (MAEC) isolated from EC-DKO mice. Mechanistically, epsins promote TNFR/TLRs signaling and NF-κB and MAPK (JNK and p38) activation by stabilizing the receptor complex formation and enhancing recruitment of NEMO, a crucial player in NF-kB activation. Conversely, epsin deficiency does not affect the surface expression of TNFR1/TLR2/4 by FACS analysis, suggesting that epsins may be dispensable for endocytosis of TNFR1/TLR2/4. We also observed that a synthetic peptide comprising the epsin ubiquitin-interacting motif (UIM) potently disrupts the association of epsins with TNFR/TLR signaling complex in vitro, suggesting a potential pharmacological inhibitory role for this peptide in controlling the atherosclerosis in vivo. Our data demonstrate that epsins control atherogenesis by regulating TNFR/TLR signaling in endothelial cells and provide a potential novel strategy to perturb atherogenesis. Conclusion Our results demonstrated an essential role of epsins in atherogenesis by regulating TNFR/TLR signaling.
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