Forced expression of microRNA-146b reduces TRAF6-dependent inflammation and improves ischemia-induced neovascularization in hypercholesterolemic conditions

被引:26
作者
Desjarlais, Michel [1 ]
Dussault, Sylvie [1 ]
Rivard, Francois [1 ]
Harel, Sharon [2 ]
Sanchez, Veronica [2 ]
Hussain, Sabah N. A. [2 ]
Rivard, Alain [1 ]
机构
[1] Ctr Hosp Univ Montreal CHUM Res Ctr, Dept Med, Montreal, PQ, Canada
[2] McGill Univ, Ctr Hlth, Dept Med, Montreal, PQ, Canada
关键词
Angiogenesis; Inflammation; Hypercholesterolemia; microRNA; Neovascularization; ENDOTHELIAL PROGENITOR CELLS; NECROSIS-FACTOR-ALPHA; THERAPEUTIC ANGIOGENESIS; INHIBITION; ATHEROSCLEROSIS; VASCULOGENESIS; MIR-146A/B; MECHANISMS; DISEASE; MICE;
D O I
10.1016/j.atherosclerosis.2019.08.010
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background and aims: MicroRNA (miR)-146 is a key regulator of inflammation, endothelial activation and atherosclerosis. This study sought to define its potential role for the modulation of ischemia-induced neovascularization in atherosclerotic conditions. Methods: Next generation sequencing and qRT-PCR analyses were used to compare microRNA expression in the ischemic muscles of hypercholesterolemic ApoE-deficient (ApoE(-/-)) mice vs. wild type mice, and in HUVECs exposed or not to oxLDL. Neovascularization was investigated in a mouse model of hindlimb ischemia and the functional activities of HUVECs and pro-angiogenic cells (PACs) were assessed in vitro. Results: We found that miR-146b (but not miR-146a) is significantly reduced in the ischemic muscles of ApoE(-/-) mice, and in HUVECs exposed to oxLDL. Inhibition of miR-146b reduces angiogenesis in vitro, whereas forced expression of miR-146b rescues oxLDL-mediated impairment of endothelial cell proliferation and tube formation. Mechanistically, miR146b directly targets tumor necrosis factor-alpha (TNFa) Receptor Associated Factor 6 (TRAF6) to inhibit inflammation. We found that hypercholesterolemia and oxLDL exposure are associated with higher levels of TRAF6, and increased expression of TNFa. However, forced expression of miR-146b in high cholesterol conditions reduces the expression of these inflammatory factors. In vivo, intramuscular injection of miR-146b mimic reduces ischemic damages and restores blood flow recuperation and capillary density in the ischemic muscles of ApoE(-/-) mice. Treatment with miR-146b also increases the number and functional activities of pro-angiogenic cells (PACs). Conclusions: Hypercholesterolemia is associated with reduced expression of miR-146b, which increases TRAF6-dependent inflammation and is associated with poor neovascularization in response to ischemia. Forced expression of miR-146b using a miR mimic could constitute a novel therapeutic strategy to improve ischemiainduced neovascularization in atherosclerotic conditions.
引用
收藏
页码:73 / 84
页数:12
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