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

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

Volume: 31 Issue: 30

Author(s): Xiao-Feng Ma, Yi-Ren Zhou, Zhi-Xiang Zhou, Hui-Ting Liu, Bo-Bin Zhou, Nian-Hua Deng, Kun Zhou, Zhen Tian, Ze-Fan Wu, Xi-Yan Liu, Ming-Gui Fu and Zhi-Sheng Jiang*

Affiliation:

• Key Laboratory for Arteriosclerosis of Hunan Province, Institute of Cardiovascular Disease, Hengyang Medical College, University of South China, Hengyang City, Hunan Province 421001, PR China

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.

Cite this article as:

Ma Xiao-Feng, Zhou Yi-Ren, Zhou Zhi-Xiang, Liu Hui-Ting, Zhou Bo-Bin, Deng Nian-Hua, Zhou Kun, Tian Zhen, Wu Ze-Fan, Liu Xi-Yan, Fu Ming-Gui and Jiang Zhi-Sheng*, TRIM65 Suppresses oxLDL-induced Endothelial Inflammation by Interaction with VCAM-1 in Atherogenesis, Current Medicinal Chemistry 2024; 31 (30) . https://dx.doi.org/10.2174/0929867331666230822152350