In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
Kurzfassung:
Background: Atherosclerosis is caused in part by endothelial dysfunction due to ER stress. Understanding the mechanisms that cause ER stress and endothelial dysfunction are essential in establishing new therapies to treat atherosclerosis. Epsins are endocytic adaptor proteins that mediate the internalization of plasma membrane receptors. However, whether epsins affect atherosclerosis remains unknown. To this end, we assessed the hypothesis that endothelial epsins play a critical role in regulating atherosclerosis. Methods and Results: In an ApoE-deficient murine model, endothelial-specific double knockout mice (EC-iDKO/ApoE-/-) significantly attenuated atherosclerotic lesion and macrophage infiltration in the aortic root and arch compared to ApoE-/- mice fed Western diet for ten weeks. To elucidate underlying mechanisms, mass spectrometry analysis identified IP3R1 as one of major interactors of epsins upon exposure to oxLDL. We show that epsins bind IP3R1 and facilitate its degradation in the endothelium. Downregulation of IP3R1 by atherosclerosis promoting agents augmented ER stress in primary mouse aortic endothelial cells. In line with these findings from mouse studies, in human atherosclerotic lesion, IP3R1 is dramatically downregulated and decrease in IP3R1 expression is associated with increased ER stress. Conversely, loss of epsins stabilized IP3R1, attenuated ER stress, reduced expression of P-selectin, adhesion molecules, and chemoattractant MCP-1 in primary mouse aortic endothelial cells. Molecular mapping analysis revealed that epsin’s UIM domain is critical in facilitating the degradation of IP3R1. Delivery of a synthetic UIM peptide conjugated with atheroma-targeting Lyp-1 peptide significantly attenuated atherosclerosis in ApoE-/- animal models by stabilizing IP3R1 and maintaining ER homeostasis. Importantly, atherosclerotic lesion was restored in EC-iDKO/ApoE-/- mice by breeding them onto an endothelial-specific IP3R1 heterozygous background, suggesting that endothelial epsins promote atheroma progression in part by mediating IP3R1 degradation. Conclusions: Our data identified a novel mechanism of epsins in regulating atherosclerosis and provide a potential target to treat atherosclerosis.
Materialart:
Online-Ressource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.37.suppl_1.212
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2017
ZDB Id:
1494427-3
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