Abstract 12274: Endothelium-specific Deletion of Epsins Attenuates Atherosclerosis Through Maintaining ER Homeostasis
Epsins are endocytotic proteins for the internalization of plasma membrane receptors. Our previous studies have suggested that epsins play an important role in tumorigenesis and lymphatic development by modulating VEGFR2, VEGFR3 or Wnt signaling. Whether epsins affect atherosclerosis remains unknown. In an ApoE-deficient murine model, endothelial-specific double knockout mice (EC-iDKO/ApoE-/-) significantly attenuated atherosclerotic lesion and macrophage infiltration in aortic root and aortic arch compared to ApoE-/- mice fed Western diet for ten weeks. Endothelium-dependent relaxation is significantly improved in epsin-deficient mice. Mechanistically, the expression of epsins is upregulated in atheroma and mouse endothelial cells in a pro-inflammatory condition, mirrored in human atherosclerotic specimen. Proteomics study using Mass spectrometry revealed that epsins bind IP3R1 and facilitate its degradation in endothelium under inflammatory condition. Downregulation of IP3R1 by athero-prone substances augmented ER stress and NFkB signaling, reversible by ER stress inhibitor 4-PBA. In line with the findings from mouse studies, IP3R1 is dramatically downregulated in human atherosclerotic endothelium. Loss of epsins stabilized IP3R1, and attenuated ER stress-dependent NFkB activation and inflammatory signaling as evidenced by the reduced expression of P-selectin, adhesion molecules, and chemoattractant MCP-1 in primary mouse aortic endothelial cells (MAEC), and reflected by in vitro rolling analysis between isolated MAEC and macrophage from mouse. Molecular modeling and mapping analysis revealed that epsin UIM is critical to facilitate the degradation of IP3R1. In conclusion, we have identified a novel molecular mechanism regarding epsins in the regulation of atherosclerosis, and our data suggest that epsins are a potential target to treat atherosclerosis.
Author Disclosures: Y. Dong: None. A. Rahman: None. X. Liu: None. H. Wu: None. M. Brophy: None. H. Chen: None.
- © 2015 by American Heart Association, Inc.