title: Therapeutic manipulation of angiogenesis with miR-27b.
abstract: BACKGROUND
  Multiple studies demonstrated pro-angiogenic effects of microRNA (miR)-27b. Its targets include Notch ligand Dll4, Sprouty (Spry)-2, PPARγ and Semaphorin (SEMA) 6A. miR-27 effects in the heart are context-dependent: although it is necessary for ventricular maturation, targeted overexpression in cardiomyocytes causes hypertrophy and dysfunction during development. Despite significant recent advances, therapeutic potential of miR-27b in cardiovascular disease and its effects in adult heart remain unexplored. Here, we assessed the therapeutic potential of miR-27b mimics and inhibitors in rodent models of ischemic disease and cancer.
  
  
  METHODS
  We have used a number of models to demonstrate the effects of miR-27b mimicry and inhibition in vivo, including subcutaneous Matrigel plug assay, mouse models of hind limb ischemia and myocardial infarction and subcutaneous Lewis Lung carcinoma.
  
  
  RESULTS
  Using mouse model of myocardial infarction due to the coronary artery ligation, we showed that miR-27b mimic had overall beneficial effects, including increased vascularization, decreased fibrosis and increased ejection fraction. In mouse model of critical limb ischemia, miR-27b mimic also improved tissue re-vascularization and perfusion. In both models, miR-27b mimic clearly decreased macrophage recruitment to the site of hypoxic injury. In contrast, miR-27b increased the recruitment of bone marrow derived cells to the neovasculature, as was shown using mice reconstituted with fluorescence-tagged bone marrow. These effects were due, at least in part, to the decreased expression of Dll4, PPARγ and IL10. In contrast, blocking miR-27b significantly decreased vascularization and reduced growth of subcutaneous tumors and decreased BMDCs recruitment to the tumor vasculature.
  
  
  CONCLUSIONS
  Our study demonstrates the utility of manipulating miR-27b levels in the treatment of cardiovascular disease and cancer.
authors.affiliation: Urology Department, Northwestern University Feinberg School of Medicine, Chicago, IL USA ; Department of Urology, University of Illinois at Chicago Medical College, Chicago, IL USA.
authors.forename: Dorina
authors.initials: D
authors.lastname: Veliceasa
authors.affiliation: Department of Medicine, Cardiology Division, Northwestern University Feinberg School of Medicine, Chicago, IL USA.
authors.forename: Dauren
authors.initials: D
authors.lastname: Biyashev
authors.affiliation: Department of Medicine, Cardiology Division, Northwestern University Feinberg School of Medicine, Chicago, IL USA.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL USA.
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.affiliation: Department of Medicine, Cardiology Division, Northwestern University Feinberg School of Medicine, Chicago, IL USA.
authors.forename: Alexander Roy
authors.initials: AR
authors.lastname: Mackie
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Urology Department, Northwestern University Feinberg School of Medicine, Chicago, IL USA ; Northwestern University, Feinberg Cardiovascular Research Institute, Chicago, IL USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
keywords: Cancer; Cardiovascular; Ischemia; Therapeutic angiogenesis; miR-27b; miRNA