Epsins Negatively Regulate Aortic Endothelial Cell Function by Augmenting Inflammatory Signaling

Background: The endothelial epsin 1 and 2 endocytic adaptor proteins play an important role in atherosclerosis by regulating the degradation of the calcium release channel inositol 1,4,5-trisphosphate receptor type 1 (IP3R1). In this study, we sought to identify additional targets responsible for epsin-mediated atherosclerotic endothelial cell activation and inflammation in vitro and in vivo. Methods: Atherosclerotic ApoE(-/-) mice and ApoE(-/-) mice with an endothelial cell-specific deletion of epsin 1 on a global epsin 2 knock-out background (EC-iDKO/ApoE(-/-)), and aortic endothelial cells isolated from these mice, were used to examine inflammatory signaling in the endothelium. Results: Inflammatory signaling was significantly abrogated by both acute (tumor necrosis factor-alpha (TNF alpha) or lipopolysaccharide (LPS)) and chronic (oxidized low-density lipoprotein (oxLDL)) stimuli in EC-iDKO/ApoE(-/-) mice and murine aortic endothelial cells (MAECs) isolated from epsin-deficient animals when compared to ApoE(-/-) controls. Mechanistically, the epsin ubiquitin interacting motif (UIM) bound to Toll-like receptors (TLR) 2 and 4 to potentiate inflammatory signaling and deletion of the epsin UIM mitigated this interaction. Conclusions: The epsin endocytic adaptor proteins potentiate endothelial cell activation in acute and chronic models of atherogenesis. These studies further implicate epsins as therapeutic targets for the treatment of inflammation of the endothelium associated with atherosclerosis.

Automated summary

This study identified epsin endocytic adaptor proteins as regulators of inflammatory signaling in atherosclerosis, facilitating endothelial cell activation in both acute and chronic models. Deletion of epsin significantly attenuated inflammatory responses in endothelial cells, indicating epsins as potential therapeutic targets for inflammation associated with atherosclerosis.