title: MicroRNA miR-27b rescues bone marrow-derived angiogenic cell function and accelerates wound healing in type 2 diabetes mellitus.
abstract: OBJECTIVE
  Vascular precursor cells with angiogenic potentials are important for tissue repair, which is impaired in diabetes mellitus. MicroRNAs are recently discovered key regulators of gene expression, but their role in vascular precursor cell-mediated angiogenesis in diabetes mellitus is unknown. We tested the hypothesis that the microRNA miR-27b rescues impaired bone marrow-derived angiogenic cell (BMAC) function in vitro and in vivo in type 2 diabetic mice.
  
  
  RESULTS
  BMACs from adult male type 2 diabetic db/db and from normal littermate db/+ mice were used. miR-27b expression was decreased in db/db BMACs. miR-27b mimic improved db/db BMAC function, including proliferation, adhesion, tube formation, and delayed apoptosis, but it did not affect migration. Elevated thrombospondin-1 (TSP-1) protein in db/db BMACs was suppressed on miR-27b mimic transfection. Inhibition of miR-27b in db/+ BMACs reduced angiogenesis, which was reversed by TSP-1 small interfering RNA (siRNA). miR-27b suppressed the pro-oxidant protein p66(shc) and mitochondrial oxidative stress, contributing to its protection of BMAC function. miR-27b also suppressed semaphorin 6A to improve BMAC function in diabetes mellitus. Luciferase binding assay suggested that miR-27b directly targeted TSP-1, TSP-2, p66(shc), and semaphorin 6A. miR-27b improved topical cell therapy of diabetic BMACs on diabetic skin wound closure, with a concomitant augmentation of wound perfusion and capillary formation. Normal BMAC therapy with miR-27b inhibition demonstrated reduced efficacy in wound closure, perfusion, and capillary formation. Local miR-27b delivery partly improved wound healing in diabetic mice.
  
  
  CONCLUSIONS
  miR-27b rescues impaired BMAC angiogenesis via TSP-1 suppression, semaphorin 6A expression, and p66shc-dependent mitochondrial oxidative stress and improves BMAC therapy in wound healing in type 2 diabetic mice.
authors.affiliation: From the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA (J.-M.W., D.-D.C., Q.D.W., A.F.C.); Vascular Surgery Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA (A.F.C.); Department of Hypertension and Vascular Disease, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (J.-M.W., J.T.); Department of Cardiology and Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China (J.-M.W., D.-D.C., J.-J.C., Q.D.W., H.Y., A.F.C.); and Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA (K.I.).
authors.forename: Jie-Mei
authors.initials: JM
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Tao
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Chen
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Cai
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
authors.forename: Qinde
authors.initials: Q
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009843:Oligoribonucleotides / Q000494:pharmacology; D018384:Oxidative Stress; D034622:RNA Interference; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014945:Wound Healing; D000099262:Thrombospondin 2
chemical_list: D018955:CD36 Antigens; D051928:CD47 Antigen; D035683:MicroRNAs; D009843:Oligoribonucleotides; D039961:Semaphorins; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2; C497895:Cd47 protein, mouse; C531388:MIRN27 microRNA, human; C540674:Mirn27 microRNA, mouse; C504203:Sema6a protein, mouse; C528034:Shc1 protein, mouse; C585483:Thbs1 protein, mouse
keywords: diabetes mellitus; microRNAs; type 2; wound healing