title: Human cardiac fibroblast extracellular matrix remodeling: dual effects of tissue inhibitor of metalloproteinase-2.
abstract: OBJECTIVE
  Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinases (MMPs) that attenuates maladaptive cardiac remodeling in ischemic heart failure. We examined the effects of TIMP-2 on human cardiac fibroblast activation and extracellular matrix (ECM) remodeling.
  
  
  METHODS
  Human cardiac fibroblasts within a three-dimensional collagen matrix were assessed for phenotype conversion, ECM architecture and key molecular regulators of ECM remodeling after differential exposure to TIMP-2 and Ala+TIMP-2 (a modified TIMP-2 analogue devoid of MMP inhibitory activity).
  
  
  RESULTS
  TIMP-2 induced opposite effects on human cardiac fibroblast activation and ECM remodeling depending on concentration. TIMP-2 activated fibroblasts into contractile myofibroblasts that remodeled ECM. At higher concentrations (>10 nM), TIMP-2 inhibited fibroblast activation and prevented ECM remodeling. As compared to profibrotic cytokine transforming growth factor (TGF)-beta1, TIMP-2 activated fibroblasts and remodeled ECM without a net accumulation of matrix elements. TIMP-2 increased total protease activity as compared to TGF-beta1. Ala+TIMP-2 exposure revealed that the actions of TIMP-2 on cardiac fibroblast activation are independent of its effects on MMP inhibition. In the presence of GM6001, a broad-spectrum MMP inhibitor, TIMP-2-mediated ECM contraction was completely abolished, indicating that TIMP-2-mediated fibroblast activation is MMP dependent.
  
  
  CONCLUSIONS
  TIMP-2 functions in a contextual fashion such that the effect on cardiac fibroblasts depends on the tissue microenvironment. These observations highlight potential clinical challenges in using TIMP-2 as a therapeutic strategy to attenuate postinjury cardiac remodeling.
authors: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Janet M C
authors: JM
authors: Ngu
authors: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Guoqi
authors: G
authors: Teng
authors: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Hans Christopher
authors: HC
authors: Meijndert
authors: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Holly E
authors: HE
authors: Mewhort
authors: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
authors: Jeannine D
authors: JD
authors: Turnbull
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors: William G
authors: WG
authors: Stetler-Stevenson
authors: Section of Cardiac Surgery, Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada. Electronic address: paul.fedak@gmail.com.
authors: Paul W M
authors: PW
authors: Fedak
mesh_terms: D020517:Atrial Appendage / Q000166:cytology / Q000378:metabolism; D064752:Atrial Remodeling / Q000502:physiology; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000502:physiology; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
chemical_list: C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020782:Matrix Metalloproteinases
keywords: Cardiac fibroblasts; Extracellular matrix; Human cells; Remodelling; TIMP-2