Matr3 reshapes m6A modification complex to alleviate macrophage inflammation during atherosclerosis

Atherosclerosis, characterized as the chronic inflammation of the arterial wall, is one of the leading causes of coronary artery disease (CAD), and macrophages are found to play essential roles in the initiation and pro-gression of inflammation in atherosclerosis. N6-methyladenosine (m6A) modification, as the most abundant epi-transcriptomic modification in mRNA, is found to mediate the atherogenic inflammatory cascades in vascular endothelium. The detailed molecular mechanism of m6A methylation regulating inflammatory response during atherosclerosis is still not fully known. In this study, we find oxidized low-density lipoprotein (oxLDL) stimu-lation increases methyltransferases Mettl3 and Mettl14 expressions in macrophages, whereas the total m6A modification level in macrophages decreases under oxLDL stimulation. Matrin-3 (Matr3), an RNA binding pro-tein, is identified to play a suppressive role on oxLDL-mediated macrophage inflammatory responses through inhibiting activation of pro-inflammatory signaling, mitogen-activated protein kinase (Mapk) by m6A-mediated mRNA decay via regulating the formation of Mettl3-Mettl14 complex. Moreover, we find that Matr3 expression decreases in the oxLDL-stimulated macrophages, and the peripheral blood-derived monocytes from patients with CAD, and overexpression of Matr3 significantly alleviates atherosclerosis development in vivo. Our study for the first time clarifies the role of Matr3 on macrophage inflammatory responses during atherosclerotic development, and supplies deep understanding on the relationship of m6A modification and inflammatory responses in atherosclerosis.

Automated summary

This study reveals the relationship between m6A modification and inflammatory responses in atherosclerosis. It is found that oxLDL stimulation increases the expression of methyltransferases while decreasing the m6A modification level in macrophages. Furthermore, Matr3 plays a suppressive role in macrophage inflammatory responses by inhibiting the activation of pro-inflammatory signaling and regulating the formation of the Mettl3-Mettl14 complex. The decreased expression of Matr3 is observed in oxLDL-stimulated macrophages and peripheral blood-derived monocytes from CAD patients, and overexpression of Matr3 significantly alleviates atherosclerosis development.