Apoptotic cell induction of miR-10b in macrophages contributes to advanced atherosclerosis progression in ApoE(-/-) mice

作者：Wang, Dongliang; Wang, Wenting; Lin, Weiqun; Yang, Wenqi; Zhang, Peiwen; Chen, Ming; Ding, Ding; Liu, Chaoqun; Zheng, Jiakun; Ling, Wenhua^*

来源：Cardiovascular Research, 2018, 114(13): 1794-1805.

DOI：10.1093/cvr/cvy132

• Atherosclerosis
• MicroRNA-10b
• Macrophage
• Apoptotic cells
• Reverse cholesterol transport

Aims We previously found that miR-10b inhibits cholesterol efflux from thioglycollate-elicited mouse peritoneal macrophages through repressing ATP binding cassette transporter (ABCA1). Herein, we deciphered the mechanism underlying macrophage miR-10b expression and the role of miR-10b in atherosclerosis.
Methods and results MiR-10b expression was increased in the arteries with advanced but not early atherosclerotic plaques of ApoE(-/-) mice. Free cholesterol-induced macrophage apoptotic cells (FC-AM) promoted miR-10b expression in mouse resident peritoneal macrophages (RPM) by up-regulation of Twist1/2 in a Mer receptor tyrosine kinase dependent manner. Surprisingly, antagomiR-10b de-repressed ABCA1 in RPM engulfing FC-AM but not in RPM alone or RPM-derived foam cells; systemic delivery of antagomiR-10b enhanced reverse cholesterol transport from RPM engulfing FC-AM but not from RPM or the foam cells in ApoE(-/-) mice. Mechanistically, RPM engulfing FC-AM possessed sufficient miR-10b functionally repressing ABCA1 expression, whereas RPM and foam cells had little miR-10b incompetently repressing ABCA1 expression. Notably, antagomiR-10b administration reduced advanced plaque size and also enhanced plaque stability in ApoE(-/-) mice, which were associated with increased plaque macrophage ABCA1 expression and reduced plaque apoptosis and inflammation. However, antagomiR-10b administration did not affect early atherosclerotic plaque formation in ApoE(-/-) mice.
Conclusion These data suggest that apoptotic cell induction of miR-10b in macrophages is important in advanced atherosclerosis progression.

• 出版日期2018-11-1
• 单位中山大学