title: Expression of the tissue inhibitor of metalloproteinase-3 by transplanted VSMCs modifies heart structure and function after myocardial infarction.
abstract: OBJECTIVE
  Extracellular matrix (ECM) remodelling is a critical aspect of cardiac remodelling following myocardial infarction. Tissue inhibitors of metalloproteinases (TIMPs) are physiological inhibitors of matrix metalloproteinases (MMPs) that degrade the ECM proteins. TIMP-3 is highly expressed in the heart and is markedly downregulated in patients with ischaemic cardiomyopathy. Cell-based gene therapy can enhance the effects of cell transplantation by temporally and spatially regulating the release of the gene product. The purpose of this study was to investigate the role of TIMP-3 gene-transfected vascular smooth muscle cells (VSMCs) in modifying heart structure and function in rats when transplanted 3days after myocardial infarction (MI).
  
  
  METHODS
  Anesthetised rats were subjected to coronary artery ligation followed 3days later by thoracotomy and transplantation of TIMP-3 gene-transfected VSMCs, untransfected VSMCs or medium injected directly into the ischaemic myocardium. We assessed left ventricular structure and function by echocardiography and morphometry, and measured the levels of myocardial matrix metalloproteinase-2 and -9 (MMP-2, MMP-9), TIMP-3 and tumour necrosis factor-α (TNF-α) at 4weeks post-myocardial infarction.
  
  
  RESULTS
  Transplantation of TIMP-3 gene-transfected VSMCs and untransfected VSMCs significantly decreased scar expansion and ventricular dilatation 25days post-transplantation (4weeks after MI). MMPs and TNF-α levels were reduced in the transplantation groups when compared to the group that was given an injection of medium only. Transplantation of TIMP-3 gene-transfected VSMCs was more effective in preventing progressive cardiac dysfunction, ventricular dilatation and in reducing MMP-2, MMP-9 and TNF-α levels when compared to the transplantation of untransfected VSMCs.
  
  
  CONCLUSIONS
  TIMP-3 gene transfection was associated with attenuated left ventricular dilation and recovery of systolic function after MI compared with the control. TIMP-3 transfection enhanced the effects of transplanted VSMCs in rats by inhibiting matrix degradation and inflammatory cytokine expression, leading to improved myocardial remodelling.
authors.affiliation: Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Zhi-Bo
authors.initials: ZB
authors.lastname: Jia
authors.affiliation: Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of Cardiothoracic Surgery, First Hospital of Qiqihaer, Qiqihaer, China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Miao
authors.affiliation: Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Kai-Yu
authors.initials: KY
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Jiang
authors.affiliation: Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: wlp5002@163.com.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Wang
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D004452:Echocardiography; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D006321:Heart / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D009203:Myocardial Infarction / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Acute myocardial infraction; Cell transplantation; Extracellular matrix; Myocardium remodeling; TIMP-3 gene