title: Downregulation of miR-223 and miR-153 mediates mechanical stretch-stimulated proliferation of venous smooth muscle cells via activation of the insulin-like growth factor-1 receptor.
abstract: Autologous venous grafts, used to circumvent occluded coronary arteries during coronary artery bypass, often develop thrombosis and neointimal hyperplasia. During neointimal hyperplasia, vascular smooth muscle cells (VSMCs), exposed to substantially higher pressure and hemodynamic forces, proliferate and extracellular matrix accumulate causing narrowing of the vessel lumen. Activation of insulin-like growth factor-1 receptor (IGF-1R) has been confirmed to be critically involved in mechanical stretch-stimulated VSMC proliferation. However, the comprehensive mechanisms responsible for activation of IGF-1R in VSMCs by mechanical stretch remain unclear. This study found that miR-223 and miR-153, targeted to IGF-1R, were down-regulated in VSMCs under stretch stress by miRNA microarray analysis in conjunction with Target Scan analysis. Overexpression of miR-223 or miR-153 down-regulated IGF-1R expression and activity in VSMCs under stretch stress. Specifically, overexpression of miR-223 and miR-153 inhibited stretch stress-enhanced VSMC proliferation and the activity of PI3K-AKT signaling. In conclusion, our study indicates that miR-153 and miR-223 are reduced in VSMCs by stretch stress, contributing to IGF-1R activation and resultant VSMC proliferation. Thus, miR-153 and miR-223 may be viable therapeutic targets for mechanical stretch-induced neointimal hyperplasia in vein grafts.
authors.affiliation: Department of Orthopaedics, First Affiliated Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.forename: Ping
authors.initials: P
authors.lastname: Duan
authors.forename: Ping
authors.initials: P
authors.lastname: Guo
authors.forename: Dianwei
authors.initials: D
authors.lastname: Li
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D001026:Coronary Artery Bypass / Q000009:adverse effects; D015536:Down-Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D058426:Neointima / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011673:Pulsatile Flow; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013141:Spiro Compounds; D013314:Stress, Mechanical; D054457:Tissue Scaffolds; D014182:Transplantation, Autologous / Q000009:adverse effects; D058017:Vascular Grafting / Q000009:adverse effects
chemical_list: D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D013141:Spiro Compounds; C529377:BAS 100; C556500:MIRN153 microRNA, human; C525067:MIR223, human; C000609258:MIRN223 microRNA, rat