MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells.

Autor: Icli B; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Wu W; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Ozdemir D; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Department of Medical Biology, Hacettepe University, Ankara, Turkey (D.O.)., Li H; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Cheng HS; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Haemmig S; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Liu X; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Giatsidis G; Division of Plastic Surgery, Department of Surgery (G.G., D.P.O.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Avci SN; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Lee N; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Guimaraes RB; Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia (ICFUC), Porto Alegre, RS, Brazil (B.G., A.M.)., Manica A; Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia (ICFUC), Porto Alegre, RS, Brazil (B.G., A.M.)., Marchini JF; Heart Institute, University of São Paulo Medical School, Brazil (J.F.M.)., Rynning SE; Department of Cardiac Surgery, LHL Hospital Gardermoen, Jessheim, Norway (S.E.R., I.R.)., Risnes I; Department of Cardiac Surgery, LHL Hospital Gardermoen, Jessheim, Norway (S.E.R., I.R.)., Hollan I; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Department of Rheumatology, Lillehammer Hospital for Rheumatic Diseases, Norway (I.H.)., Croce K; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Yang X; AM Biotechnologies, LLC, Houston, TX (X.Y.)., Orgill DP; Division of Plastic Surgery, Department of Surgery (G.G., D.P.O.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Feinberg MW; From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Jazyk: angličtina
Zdroj: Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2019 Jul; Vol. 39 (7), pp. 1458-1474. Date of Electronic Publication: 2019 May 16.
DOI: 10.1161/ATVBAHA.119.312726
Abstrakt: Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.
Databáze: MEDLINE