Abstract 12764: Endothelial-Specific Deletion of Epsins Attenuates Atherosclerosis in ApoE-Deficient Mouse Model
Objective: Epsins are ubiquitin-binding endocytic adaptor proteins and regulate membrane receptor signaling. The current study aims to investigate the molecular mechanism by which epsins regulate atherosclerosis.
Methods: Tamoxifen-inducible Cre-driven global or constitutive Ve-cadherin Cre-driven endothelial-cell specific epsin 1 and 2 double knockout mice, iDKO or EC-DKO, respectively in ApoE-/- background were established and fed western diet (WD) for ten weeks. Aortic lesions were analyzed by histology and oil red O staining. Molecular mechanism was determined by molecular, cellular, biochemical and genetic approaches.
Results: En face analysis revealed that global epsin deletion in ApoE-/- mice significantly reduced atherosclerotic lesion area in aorta compared to control ApoE-/- mice. Similar results were obtained in aortic root by oil red O staining. Similarly, EC-DKO/ApoE-/- mice exhibited substantially reduced atherosclerotic lesion burden with significantly improved endothelial-dependent relaxation. In primary mouse aortic EC (MAEC), TNFα and LPS-induced upregulation of P-selectin, ICAM1 and VCAM1 were remarkably attenuated by loss of epsins, leading to impaired rolling of WT macrophage on epsin deleted MAEC using an in vitro rolling assay. Furthermore, TNFα, LPS or ox-LDL stimulated P-NFkb, P-JNK and P-p38 signaling is drastically attenuated. Additionally, macrophage chemoattractant, MCP-1, was also downregulated in epsin deleted MAEC compared to WT, consistent with impaired macrophage infiltration of the atheroma in EC-iDKO/ApoE-/- mice analyzed by Moma-2 immunofluorescence staining and FACS analysis of immune and inflammatory cells composition in aorta. These results suggested that epsins play critical role in the atherogenesis by potentiating endothelium activation. Furthermore, epsin expression in atheroma is upregulated in ApoE-/- mice fed WD, a result mirrored in human atherosclerotic specimens.
Conclusion: We conclude that epsins play a critical role in promoting atherogenesis through potentiating endothelium activation and leukocyte-endothelial interaction during atherosclerosis. Our findings may implicate a potential new therapeutic strategy for atherosclerosis treatment.
Author Disclosures: Y. Dong: None. S. Pasula: None. H. Song: None. M. Brophy: None. X. Liu: None. X. Cai: None. H. Chen: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.