title: MiR-129-5p-mediated Beclin-1 suppression inhibits endothelial cell autophagy in atherosclerosis.
abstract: Endothelial cell injury and subsequent death play an essential role in the pathogenesis of atherosclerosis. Autophagy of endothelial cells antagonizes the development of atherosclerosis, whereas the underlying molecular mechanisms are unclear. MicroRNA-129-5p (miR-129-5p) is a well-defined tumor suppressorin some types of cancer, while it is unknown whether miR-129-5p may also play a role in the development of atherosclerosis. Here, we addressed this question in the current study. We examined the levels of endothelial cell autophagy in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of Beclin-1 and the levels of miR-129-5p in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-129-5p and 3'-UTR of Beclin-1 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-129-5p were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). We found that HFD mice developed atherosclerosisin 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as CTL mice) did not. Compared to CTL mice, HFD mice had significantly lower levels of endothelial cell autophagy, resulting from decreases in Beclin-1 protein, but not mRNA. The decreases in Beclin-1 in endothelial cells were due to HFD-induced increases inmiR-129-5p, which suppressed the translation of Beclin-1 mRNA via 3'-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. Together, these data suggest that upregulation of miR-129-5p by HFD may impair the protective effects of endothelial cell autophagy against development of atherosclerosis through suppressing protein translation of Beclin-1.
authors.affiliation: Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University Chongqing 400037, China.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Geng
authors.affiliation: Oncology Radiotherapy Center of PLA 302 Hospital Beijing 100039, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Josephine Ford Cancer Center, Department of Internal Medicine, Henry Ford Health System Detroit, MI 48202, USA.
authors.forename: Yiguan
authors.initials: Y
authors.lastname: Zhang
keywords: ApoE (-/-); Atherosclerosis; Beclin-1; endothelial cell autophagy; high fat diet (HFD); miR-129-5p; ox-LDL