A MicroRNA93–Interferon Regulatory Factor-9–Immunoresponsive Gene-1–Itaconic Acid Pathway Modulates M2-Like Macrophage Polarization to Revascularize Ischemic Muscle

• DOI: 10.1161/circulationaha.116.025490
• Publication Date: 2017-03-30T00:30:29Z
• Authors: Vijay Chaitanya G...; Min Hyub Choi; Anna Kutateladze; Todd E. Fox; Charles R. Farber; Brian H. Annex
• Keywords: Arteriogenesis; Macrophage polarization

Background: Currently, no therapies exist for treating and improving outcomes in patients with severe peripheral artery disease (PAD). MicroRNA93 (miR93) has been shown to favorably modulate angiogenesis reduce tissue loss genetic PAD models. However, the cell-specific function, downstream mechanisms, or signaling involved miR93-mediated ischemic muscle neovascularization is not clear. Macrophages were best known arteriogenic response PAD, extent of induced by macrophages dependent on greater M2 M1 activation/polarization state. In present study, we identified a novel mechanism which miR93 regulates macrophage polarization promote arteriogenesis revascularize experimental PAD. Methods: vitro (macrophages, endothelial cells, skeletal cells under normal hypoxia serum starvation conditions) vivo experiments preclinical models (unilateral femoral ligation resection) conducted examine role miR93-interferon regulatory factor-9–immunoresponsive gene-1 (IRG1)–itaconic acid pathway polarization, angiogenesis, arteriogenesis, perfusion recovery. Results: vivo, compared wild-type controls, miR106b-93-25 cluster–deficient mice (miR106b-93-25 −/− ) showed decreased correlating increased M1-like after Intramuscular delivery perfusion, correlated more M2-like proximal distal hind-limb muscles. vitro, promotes sustains even polarizing conditions (hypoxia starvation). Delivery bone marrow–derived from whereas transfer had opposite effect. Systematic analysis top differentially upregulated genes RNA sequencing between that IRG1 function itaconic production polarization. The 3′ untranslated region luciferase assays performed determine whether direct target revealed an but interferon factor-9, can regulate expression, target. expression factor-9 treatment significantly angiogenic potential. Conclusions: inhibits decrease IRG1–itaconic induce enhance recovery