title: Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling.
abstract: BACKGROUND
  Tissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Sustained elevation of pro-fibrotic cytokine transforming growth factor-beta1 (TGFβ1) induces cardiac myofibroblast-mediated fibrosis and progressive structural tissue remodeling.
  
  
  OBJECTIVE
  We examined the effects of low molecular weight fibroblast growth factor (LMW-FGF-2) on human cardiac myofibroblast-mediated extracellular matrix (ECM) dysregulation and remodeling.
  
  
  METHODS
  Human cardiac biopsies were obtained during open-heart surgery and myofibroblasts were isolated, passaged, and seeded within type I collagen matrices. To induce myofibroblast activation and ECM remodeling, myofibroblast-seeded collagen gels were exposed to TGFβ1. The extent of ECM contraction, myofibroblast activation, ECM dysregulation, and cell apoptosis was determined in the presence of LMW-FGF-2 and compared to its absence. Using a novel floating nylon-grid supported thin collagen gel culture platform system, myofibroblast activation and local ECM remodeling around isolated single cells was imaged using confocal microscopy and quantified by image analysis.
  
  
  RESULTS
  TGFβ1 induced significant myofibroblast activation and ECM dysregulation as evidenced by collagen gel contraction, structural ECM remodeling, collagen synthesis, ECM degradation, and altered TIMP expression. LMW-FGF-2 significantly attenuated TGFβ1 induced myofibroblast-mediated ECM remodeling. These observations were similar using either ventricular or atrial-derived cardiac myofibroblasts. In addition, for the first time using individual cells, LMW-FGF-2 was observed to attenuate cardiac myofibroblast activation and prevent local cell-mediated ECM perturbations.
  
  
  CONCLUSIONS
  LMW-FGF-2 attenuates human cardiac myofibroblast-mediated ECM remodeling and may prevent progressive maladaptive chamber remodeling and tissue fibrosis for patients with diverse structural heart diseases.
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. d.svstnk@gmail.com.
authors.forename: Daniyil A
authors.initials: DA
authors.lastname: Svystonyuk
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. janet.ngu1020@gmail.com.
authors.forename: Janet M C
authors.initials: JM
authors.lastname: Ngu
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. hollymewhort@me.com.
authors.forename: Holly E M
authors.initials: HE
authors.lastname: Mewhort
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. brodie_dl@hotmail.com.
authors.forename: Brodie D
authors.initials: BD
authors.lastname: Lipon
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. teng@ucalgary.ca.
authors.forename: Guoqi
authors.initials: G
authors.lastname: Teng
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. dgguzzardi@gmail.com.
authors.forename: David G
authors.initials: DG
authors.lastname: Guzzardi
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. m.getanshu@gmail.com.
authors.forename: Getanshu
authors.initials: G
authors.lastname: Malik
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. dbelke@ucalgary.ca.
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Belke
authors.affiliation: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, C880, 1403 29 Street NW, Calgary, Alberta, T2N 2T9, Canada. paul.fedak@gmail.com.
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
mesh_terms: D017209:Apoptosis; D001706:Biopsy; D002454:Cell Differentiation; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005355:Fibrosis; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D003094:Collagen