title: MicroRNA let-7g possesses a therapeutic potential for peripheral artery disease.
abstract: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and conveys a significant health burden globally. Critical limb ischaemia encompasses the most severe consequence of PAD. Our previous studies indicate that microRNA let-7g prevents atherosclerosis and improves endothelial functions. This study aimed to investigate whether and how let-7g therapy may improve blood flow to ischaemic limbs. The present study shows that let-7g has multiple pro-angiogenic effects on mouse ischaemic limb model and could be a potential therapeutic agent for PAD. Mice receiving intramuscular injection of let-7g had more neovascularization, better local perfusion and increased recruitment of endothelial progenitor cells after hindlimb ischaemia. The therapeutic effects of let-7g's on angiogenesis are mediated by multiple regulatory machinery. First, let-7g increased expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR-2) through targeting their upstream regulators HIF-3α and TP53. In addition, let-7g affected the splicing factor SC35 which subsequently enhanced the alternative splicing of VEGF-A from the anti-angiogenic isoform VEGF-A165btowards the pro-angiogenic isoform VEGF-A164a. The pleiotropic effects of let-7g on angiogenesis imply that let-7g may possess a therapeutic potential in ischaemic diseases.
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Hsu
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Edward
authors.initials: E
authors.lastname: Hsi
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Wang
authors.affiliation: Department of Neurology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ruey-Tay
authors.initials: RT
authors.lastname: Lin
authors.affiliation: Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.|Department of Neurology, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
authors.forename: Suh-Hang H
authors.initials: SH
authors.lastname: Juo
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy; D002460:Cell Line; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000187:drug effects*; D006614:Hindlimb / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D058729:Peripheral Arterial Disease / Q000188:drug therapy* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D043925:Angiogenesis Inducing Agents; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: angiogenesis; endothelial progenitor cells; microRNA let-7g; peripheral artery disease; vascular endothelial growth factor-A