Abstract 15914: Conditional Deletion of Epsins Attenuates Atherosclerosis in ApoE-Deficient Mouse Model
Objective: Epsins are adaptor proteins implicated in clathrin-mediated endocytosis and membrane receptor signaling. Global deletion of epsins in mice causes embryonic lethality. Whether epsins are involved in atherosclerosis remain completely unknown. Current study aims to investigate the role of epsins in atherosclerosis. We hypothesize that epsins are important regulators for the expression of selectins, adhesion molecules and chemoattractant MCP-1 in endothelial cells and immune cells, and consequently promote atherogenesis.
Methods: The tamoxifen inducible global epsin 1 and 2 double knockout (iDKO) mouse in ApoE-/- genetic background has been established and fed with high fat diet (HFD) for 12 weeks. Aortic lesions were analyzed by histology and oil red O staining. Expression of selectins, adhesion molecules and chemoattractant were analyzed by western blot or real time PCR (RT-PCR).
Results: Epsin-deficient mice exhibit significantly reduced atherosclerotic lesion area in aortic root and arch compared to ApoE-/- mice (n=6-8, P<0.05). In primary mouse EC (MEC) culture, deletion of epsins greatly decreases the expression of P-selectin and adhesion molecules VCAM. Furthermore, TNFα and LPS induced upregulation of P- & E-selectins as well as ICAM, and VCAM are remarkably attenuated by loss of epsins (n=4, P<0.01). Conversely, chemoattractant MCP-1 is also downregulated in DKO MEC compared to WT. Downregulation of epsins in monocytes significantly inhibited TNFα- or LPS-stimulated cell migration (n=3, P<0.01).
Conclusion: Our data provide the initial evidence that epsins may play a critical role in promoting atherogenesis through increasing endothelial cell surface expression of selectins, adhesion molecules and chemoattractans, resulting in enhanced recruitment of myeloid cells to the endothelial wall and leading to atherosclerotic lesions under high fat diet condition. Our finding may implicate a potential new therapeutic strategy for atherosclerosis treatment.
- © 2011 by American Heart Association, Inc.