title: Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress.
abstract: BACKGROUND
  Remodeling of the extracellular matrix (ECM) is a key aspect of myocardial response to biomechanical stress and heart failure. Tissue inhibitors of metalloproteinases (TIMPs) regulate the ECM turnover through negative regulation of matrix metalloproteinases (MMPs), which degrade the ECM structural proteins. Tissue inhibitor of metalloproteinases 2 is unique among TIMPs in activating pro-MMP2 in addition to inhibiting a number of MMPs. Given this dual role of TIMP2, we investigated whether TIMP2 serves a critical role in heart disease.
  
  
  RESULTS
  Pressure overload by transverse aortic constriction (TAC) in 8-week-old male mice resulted in greater left ventricular hypertrophy, fibrosis, dilation, and dysfunction in TIMP2-deficient (TIMP2(-/-)) compared with wild-type mice at 2 weeks and 5 weeks post-TAC. Despite lack of MMP2 activation, total collagenase activity and specific membrane type MMP activity were greater in TIMP2(-/-)-TAC hearts. Loss of TIMP2 resulted in a marked reduction of integrin β1D levels and compromised focal adhesion kinase phosphorylation, resulting in impaired adhesion of cardiomyocytes to ECM proteins, laminin, and fibronectin. Nonuniform ECM remodeling in TIMP2(-/-)-TAC hearts revealed degraded network structure as well as excess fibrillar deposition. Greater fibrosis in TIMP2(-/-)-TAC compared with wild-type TAC hearts was due to higher levels of SPARC (secreted protein acidic and rich in cysteine) and posttranslational stabilization of collagen fibers rather than increased collagen synthesis. Inhibition of MMPs including membrane type MMP significantly reduced left ventricular dilation and dysfunction, hypertrophy, and fibrosis in TIMP2(-/-)-TAC mice.
  
  
  CONCLUSIONS
  Lack of TIMP2 leads to exacerbated cardiac dysfunction and remodeling after pressure overload because of excess activity of membrane type MMP and loss of integrin β1D, leading to nonuniform ECM remodeling and impaired myocyte-ECM interaction.
authors: Assistant Professor, Department of Physiology, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada.
authors: Vijay
authors: V
authors: Kandalam
authors: Ratnadeep
authors: R
authors: Basu
authors: Linn
authors: L
authors: Moore
authors: Dong
authors: D
authors: Fan
authors: Xiuhua
authors: X
authors: Wang
authors: Diane M
authors: DM
authors: Jaworski
authors: Gavin Y
authors: GY
authors: Oudit
authors: Zamaneh
authors: Z
authors: Kassiri
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D004195:Disease Models, Animal; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019012:Integrin beta1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013314:Stress, Mechanical; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D019012:Integrin beta1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse