Seema Dangwal1, Bernd Stratmann1, Claudia Bang1, Johan M Lorenzen1, Regalla Kumarswamy1, Jan Fiedler1, Christine S Falk1, Claus J Scholz1, Thomas Thum2, Diethelm Tschoepe1. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Andrew S Kimball; Amrita Joshi; William F Carson; Anna E Boniakowski; Matthew Schaller; Ronald Allen; Jennifer Bermick; Frank M Davis; Peter K Henke; Charles F Burant; Steve L Kunkel; Katherine A Gallagher Journal: Diabetes Date: 2017-06-29 Impact factor: 9.461
Authors: Austin P Veith; Kayla Henderson; Adrianne Spencer; Andrew D Sligar; Aaron B Baker Journal: Adv Drug Deliv Rev Date: 2018-09-26 Impact factor: 15.470
Authors: Basak Icli; Christoph S Nabzdyk; Jorge Lujan-Hernandez; Meghan Cahill; Michael E Auster; A K M Wara; Xinghui Sun; Denizhan Ozdemir; Giorgio Giatsidis; Dennis P Orgill; Mark W Feinberg Journal: J Mol Cell Cardiol Date: 2016-01-09 Impact factor: 5.000