title: Loss of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity.
abstract: BACKGROUND
  MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34(+) cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34(+) cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity.
  
  
  RESULTS
  Angiogenic EOCs and CD34(+) cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34(+) cells. Anti-miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function.
  
  
  CONCLUSIONS
  The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34(+) cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection.
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Jakob
authors.forename: Carola
authors.initials: C
authors.lastname: Doerries
authors.forename: Sylvie
authors.initials: S
authors.lastname: Briand
authors.forename: Pavani
authors.initials: P
authors.lastname: Mocharla
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kränkel
authors.forename: Christian
authors.initials: C
authors.lastname: Besler
authors.forename: Maja
authors.initials: M
authors.lastname: Mueller
authors.forename: Costantina
authors.initials: C
authors.lastname: Manes
authors.forename: Christian
authors.initials: C
authors.lastname: Templin
authors.forename: Christof
authors.initials: C
authors.lastname: Baltes
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
authors.forename: Heiner
authors.initials: H
authors.lastname: Adams
authors.forename: Mathias
authors.initials: M
authors.lastname: Wolfrum
authors.forename: Georg
authors.initials: G
authors.lastname: Noll
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D002908:Chronic Disease; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology; D018919:Neovascularization, Physiologic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527111:MIRN126 microRNA, human; C554019:MIRN130 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C504812:SPRED1 protein, human