TRIM65 Suppresses oxLDL-induced Endothelial Inflammation by Interaction with VCAM-1 in Atherogenesis


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Abstract

Background and Objective:Endothelial cell activation, characterized by increased levels of vascular cell adhesion molecule 1 (VCAM-1), plays a crucial role in the development of atherosclerosis (AS). Therefore, inhibition of VCAM-1-mediated inflammatory response is of great significance in the prevention and treatment of AS. The tripartite motif (TRIM) protein-TRIM65 is involved in the regulation of cancer development, antivirals and inflammation. We aimed to study the functions of TRIM65 in regulating endothelial inflammation by interacting with VCAM-1 in atherogenesis.

Methods and Results:In vitro, we report that human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (oxLDL) significantly upregulate the expression of TRIM65 in a time- and dose-dependent manner. Overexpression of TRIM65 reduces oxLDL-triggered VCAM-1 protein expression, decreases monocyte adhesion to HUVECs and inhibits the production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α as well as endothelial oxLDL transcytosis. In contrast, siRNA-mediated knockdown of TRIM65 promotes the expression of VCAM-1, resulting in increased adhesion of monocytes and the release of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α and enhances endothelial oxLDL transcytosis. In vivo, we measured the high expression of TRIM65 in ApoE-/- mouse aortic plaques compared to C57BL/6J mouse aortic plaques. Then, we examined whether the blood levels of VCAM-1 were higher in TRIM65 knockout ApoE-/- mice than in control mice induced by a Western diet. Furthermore, Western blot results showed that the protein expression of VCAM-1 was markedly enhanced in TRIM65 knockout ApoE-/- mouse aortic tissues compared to that of the controls. Immunofluorescence staining revealed that the expression of VCAM-1 was significantly increased in atherosclerotic plaques of TRIM65-/-/ApoE-/- aortic vessels compared to ApoE-/- controls. Mechanistically, TRIM65 specifically interacts with VCAM-1 and targets it for K48-linked ubiquitination.

Conclusion:Our studies indicate that TRIM65 attenuates the endothelial inflammatory response by targeting VCAM-1 for ubiquitination and provides a potential therapeutic target for the inhibition of endothelial inflammation in AS.

About the authors

Xiao-Feng Ma

Department of Cardiology, Affiliated Nanhua Hospital, University of South China

Email: info@benthamscience.net

Yi-Ren Zhou

Department of Cardiology, Affiliated Nanhua Hospital, University of South China

Email: info@benthamscience.net

Zhi-Xiang Zhou

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Hui-Ting Liu

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Bo-Bin Zhou

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Nian-Hua Deng

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Kun Zhou

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Zhen Tian

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Ze-Fan Wu

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Xi-Yan Liu

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Email: info@benthamscience.net

Ming-Gui Fu

Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City

Email: info@benthamscience.net

Zhi-Sheng Jiang

Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China

Author for correspondence.
Email: info@benthamscience.net

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