miR-146a contributes to atherosclerotic plaque stability by regulating the expression of TRAF6 and IRAK-1.

Abstract

BACKGROUND:

Atherosclerosis is a chronic inflammatory disease. The vulnerable plaque of atherosclerotic can lead to the development of many diseases including acute coronary syndrome and coronary heart disease. It is well known that miR-146a is the key brake miRNA of the inflammatory signal transduction pathway. However, the effect of miR-146a on the stability of atherosclerotic plaque remains to be elucidated.

METHODS AND RESULTS:

We constructed animal models of atherosclerosis and foam cell models, and overexpressed and knocked-down miR-146a in models. After staining with Hematoxylin-Eosin (HE), Oil Red O, immunocytochemistry (IHC) and Sirius Red, we used the proportion of (Lipids area + Macrophage area) and (SMCs area + collagen area) to evaluate atherosclerotic plaque stability. TUNEL and flow cytometry were performed to detect the apoptosis level of macrophages. Levels of inflammatory factors were detected via ELISA assay. The results showed that miR-146a, IRAK1 and TRAF6 were abnormally expressed in plaques of atherosclerotic animals. Overexpression of miR-146a contributed to the stability of plaques that inhibited plaque formation, macrophage apoptosis and levels of pro-inflammatory factors. The Dual-luciferase reporter gene assay, IF and FISH were used to verify the regulatory mechanism of miR-146a on IRAK1 and TRAF6. We found that IRAK1 and TRAF6 promoted lipid uptake, apoptosis, and release of pro-inflammatory factors of RAW264.7 macrophages, whereas miR-146a restored RAW264.7 macrophages phenotype by inhibiting IRAK1 and TRAF6 expression.

CONCLUSIONS:

We display for the first time that miR-146a inhibits the formation of foam cells, RAW264.7 macrophage apoptosis and pro-inflammatory reaction through negative regulation of IRAK1 and TRAF6 expression, thereby enhancing the stability of atherosclerotic plaques.

• Authors: Tianshu Chu, Xu Xu, Zhimin Ruan, Liyong Wu, Mingli Zhou, Guofu Zhu
• Journal: Molecular biology reports (Mol Biol Rep) Vol. 49 Issue 6 Pg. 4205-4216 (Jun 2022) ISSN: 1573-4978 [Electronic] Netherlands
• PMID: 35195809 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• MicroRNAs
• TNF Receptor-Associated Factor 6

Topics

• Animals
• Atherosclerosis (genetics)
• MicroRNAs (metabolism)
• Plaque, Atherosclerotic (genetics)
• Signal Transduction
• TNF Receptor-Associated Factor 6 (genetics, metabolism, pharmacology)