title: Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury: Role of Human CD34+ Cells Deficient in MicroRNA-377.
abstract: MicroRNA (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress.
  
  
  
  The aim of this study was to explore the role of miR in human CD34(+) cell (hCD34(+)) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions.
  
  
  
  In response to inflammatory stimuli, the miR array profile of endothelial progenitor cells was analyzed using a polymerase chain reaction-based miR microarray. miR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on an hCD34(+) cell angiogenic proteome profile in vitro and on cardiac repair and function after I-R injury in immunodeficient mice.
  
  
  
  The miR array data from endothelial progenitor cells in response to inflammatory stimuli indicated changes in numerous miR, with a robust decrease in the levels of miR-377. Human cardiac biopsies from patients with HF showed significant increases in miR-377 expression compared with nonfailing control hearts. The proteome profile of hCD34(+) cells transfected with miR-377 mimics showed significant decrease in the levels of proangiogenic proteins versus nonspecific control-transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377 silenced hCD34(+) cells in immunodeficient mice, promoting neovascularization (at 28 days, post-I-R) and lower interstitial fibrosis, leading to improved left ventricular function.
  
  
  
  These findings indicate that HF increased miR-377 expression in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34(+) cells into ischemic myocardium promoted their angiogenic ability, attenuating left ventricular remodeling and cardiac fibrosis.
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Darukeshwara
authors.initials: D
authors.lastname: Joladarashi
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Venkata Naga Srikanth
authors.initials: VNS
authors.lastname: Garikipati
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Mackie
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gumpert
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas.
authors.forename: Arvind
authors.initials: A
authors.lastname: Bhimaraj
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Youker
authors.affiliation: Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas.
authors.forename: Cesar
authors.initials: C
authors.lastname: Uribe
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Sahana
authors.initials: S
authors.lastname: Suresh Babu
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Prince
authors.initials: P
authors.lastname: Jeyabal
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas; Department of Cell and Developmental Biology, Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, New York. Electronic address: pkrishnamurthy@houstonmethodist.org.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
mesh_terms: D000328:Adult; D000818:Animals; D018952:Antigens, CD34; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D005260:Female; D006321:Heart; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018952:Antigens, CD34; C534063:MIRN377 microRNA, human; D035683:MicroRNAs
keywords: endothelial progenitor cells; heart failure; neovascularization