title: Resistin Promotes Angiogenesis in Endothelial Progenitor Cells Through Inhibition of MicroRNA206: Potential Implications for Rheumatoid Arthritis.
abstract: Endothelial progenitor cells (EPCs) promote angiogenesis and are therefore key contributors to a wide variety of angiogenesis-related autoimmune diseases such as rheumatoid arthritis (RA). However, the signaling mechanisms through which these progenitor cells influence RA pathogenesis remain unknown. The aim of this study was to examine whether resistin plays a role in the pathogenesis of and angiogenesis associated with RA by circulating EPCs. We found that levels of resistin in synovial fluid and tissue from patients with RA and from mice with collagen-induced arthritis were overexpressed and promoted the homing of EPCs into the synovium, thereby inducing angiogenesis. EPCs isolated from healthy donors were used to investigate the signal transduction pathway underlying EPC migration and tube formation after treatment with resistin. We found that resistin directly induced a significant increase in expression of vascular endothelial growth factor (VEGF) in EPCs. We also found that the expression of microRNA-206 (miR-206) was negatively correlated with the expression of resistin during EPC-mediated angiogenesis. Notably, the increased expression of VEGF was associated with decreased binding of miR-206 to the VEGF-A 3' untranslated region through protein kinase C delta-dependent AMP-activated protein kinase signaling pathway. Moreover, blockade of resistin reduced EPC homing into synovial fluid and angiogenesis in vivo. Taken together, our study is the first to demonstrate that resistin promotes EPCs homing into the synovium during RA angiogenesis via a signal transduction pathway that involves VEGF expression in primary EPCs. These findings provide support for resistin as a therapeutic target for the patients with RA. Stem Cells 2015;33:2243-2255.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Su
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.|Department of Orthopedic Surgery, China Medical University, Taichung, Taiwan.
authors.forename: Chin-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Orthopedic Surgery, China Medical University, Taichung, Taiwan.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yun-Lin County, Taiwan.
authors.forename: Chun-Yin
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000328:Adult; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism*; D002642:Chick Embryo; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D052243:Resistin; D014162:Transfection
chemical_list: D035683:MicroRNAs; D052243:Resistin
keywords: Collagen-induced arthritis; Endothelial progenitor cell; MicroRNA; Resistin; Rheumatoid arthritis