Title:TRIM65 Suppresses oxLDL-induced Endothelial Inflammation by
Interaction with VCAM-1 in Atherogenesis
Volume: 31
Issue: 30
关键词:
TRIM65，动脉粥样硬化，内皮炎症，VCAM-1，单核细胞粘附，泛素化。
摘要: 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.
