1 Ocak 2019 Dergi makalesi Açık Erişim

Icli, Basak; Wu, Winona; Ozdemir, Denizhan; Li, Hao; Cheng, Henry S.; Haemmig, Stefan; Liu, Xin; Giatsidis, Giorgio; Avci, Seyma Nazli; Lee, Nathan; Guimaraes, Raphael Boesch; Manica, Andre; Marchini, Julio F.; Rynning, Stein Erik; Risnes, Ivar; Hollan, Ivana; Croce, Kevin; Yang, Xianbin; Orgill, Dennis P.; Feinberg, Mark W.

Citation Style Language JSON

{
  "DOI": "10.1161/ATVBAHA.119.312726", 
  "abstract": "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.", 
  "author": [
    {
      "family": "Icli", 
      "given": " Basak"
    }, 
    {
      "family": "Wu", 
      "given": " Winona"
    }, 
    {
      "family": "Ozdemir", 
      "given": " Denizhan"
    }, 
    {
      "family": "Li", 
      "given": " Hao"
    }, 
    {
      "family": "Cheng", 
      "given": " Henry S."
    }, 
    {
      "family": "Haemmig", 
      "given": " Stefan"
    }, 
    {
      "family": "Liu", 
      "given": " Xin"
    }, 
    {
      "family": "Giatsidis", 
      "given": " Giorgio"
    }, 
    {
      "family": "Avci", 
      "given": " Seyma Nazli"
    }, 
    {
      "family": "Lee", 
      "given": " Nathan"
    }, 
    {
      "family": "Guimaraes", 
      "given": " Raphael Boesch"
    }, 
    {
      "family": "Manica", 
      "given": " Andre"
    }, 
    {
      "family": "Marchini", 
      "given": " Julio F."
    }, 
    {
      "family": "Rynning", 
      "given": " Stein Erik"
    }, 
    {
      "family": "Risnes", 
      "given": " Ivar"
    }, 
    {
      "family": "Hollan", 
      "given": " Ivana"
    }, 
    {
      "family": "Croce", 
      "given": " Kevin"
    }, 
    {
      "family": "Yang", 
      "given": " Xianbin"
    }, 
    {
      "family": "Orgill", 
      "given": " Dennis P."
    }, 
    {
      "family": "Feinberg", 
      "given": " Mark W."
    }
  ], 
  "container_title": "ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY", 
  "id": "112080", 
  "issue": "7", 
  "issued": {
    "date-parts": [
      [
        2019, 
        1, 
        1
      ]
    ]
  }, 
  "page": "1458-1474", 
  "title": "MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells", 
  "type": "article-journal", 
  "volume": "39"
}