Epsins Negatively Regulate Aortic Endothelial Cell Function by Augmenting Inflammatory Signaling.

Abstract

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-α (TNFα) 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.

• Authors: Yunzhou Dong, Beibei Wang, Kui Cui, Xiaofeng Cai, Sudarshan Bhattacharjee, Scott Wong, Douglas B Cowan, Hong Chen
• Journal: Cells (Cells) Vol. 10 Issue 8 (07 29 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34440686 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Vesicular Transport
• Epn2 protein, mouse
• Lipoproteins, LDL
• epsin
• oxidized low density lipoprotein

Topics

• Adaptor Proteins, Vesicular Transport (metabolism)
• Animals
• Aorta (metabolism)
• Atherosclerosis (etiology, metabolism)
• Endothelial Cells (metabolism, pathology)
• Female
• Inflammation
• Lipoproteins, LDL (metabolism)
• Male
• Mice
• Mice, Knockout
• Signal Transduction