title: Impairment of Wound Healing in Patients With Type 2 Diabetes Mellitus Influences Circulating MicroRNA Patterns via Inflammatory Cytokines.
abstract: OBJECTIVE
  MicroRNAs (miRNA/miR) are stably present in body fluids and are increasingly explored as disease biomarkers. Here, we investigated influence of impaired wound healing on the plasma miRNA signature and their functional importance in patients with type 2 diabetes mellitus.
  
  
  RESULTS
  miRNA array profiling identified 41 miRNAs significantly deregulated in diabetic controls when compared with patients with diabetes mellitus-associated peripheral arterial disease and chronic wounds. Quantitative real-time polymerase chain reaction validation confirmed decrease in circulating miR-191 and miR-200b levels in type 2 diabetic versus healthy controls. This was reverted in diabetic subjects with associated peripheral arterial disease and chronic wounds, who also exhibited higher circulating C-reactive protein and proinflammatory cytokine levels compared with diabetic controls. miR-191 and miR-200b were significantly correlated with C-reactive protein or cytokine levels in patients with diabetes mellitus. Indeed, proinflammatory stress increased endothelial- or platelet-derived secretion of miR-191 or miR-200b. In addition, dermal cells took up endothelial-derived miR-191 leading to downregulation of the miR-191 target zonula occludens-1. Altered miR-191 expression influenced angiogenesis and migratory capacities of diabetic dermal endothelial cells or fibroblasts, respectively, partly via its target zonula occludens-1.
  
  
  CONCLUSIONS
  This study reports that (1) inflammation underlying nonhealing wounds in patients with type 2 diabetes mellitus influences plasma miRNA concentrations and (2) miR-191 modulates cellular migration and angiogenesis via paracrine regulation of zonula occludens-1 to delay the tissue repair process.
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Seema
authors: S
authors: Dangwal
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Bernd
authors: B
authors: Stratmann
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Claudia
authors: C
authors: Bang
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Johan M
authors: JM
authors: Lorenzen
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Regalla
authors: R
authors: Kumarswamy
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Jan
authors: J
authors: Fiedler
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Christine S
authors: CS
authors: Falk
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Claus J
authors: CJ
authors: Scholz
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.). thum.thomas@mh-hannover.de.
authors: Thomas
authors: T
authors: Thum
authors: From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (S.D., C.B., J.M.L., R.K., J.F., T.T.), Integrated Research and Treatment Center Transplantation, IFB-Tx (J.M.L., C.S.F., T.T.), and Institute of Transplant Immunology (C.S.F.), Hannover Medical School, Hannover, Germany; Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany (B.S., D.T.); IZKF Laboratory for Microarray Applications, University Hospital of Wuerzburg, Wuerzburg, Germany (C.J.S.); and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.).
authors: Diethelm
authors: D
authors: Tschoepe
mesh_terms: D000368:Aged; D001792:Blood Platelets / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002465:Cell Movement; D016207:Cytokines / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D003925:Diabetic Angiopathies / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D058729:Peripheral Arterial Disease / Q000097:blood; D040081:Protein Array Analysis; D014945:Wound Healing
chemical_list: D016207:Cytokines; C546177:MIRN191 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D002097:C-Reactive Protein
keywords: diabetes mellitus, type 2; inflammation; microRNAs; peripheral arterial disease; wound healing; zonula occludens-1 protein