title: Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction.
abstract: OBJECTIVE
  Tissue inhibitor of metalloproteinases (TIMPs) can mediate myocardial remodelling, hypertrophy, and fibrosis in heart disease. We investigated the impact of TIMP2 vs. TIMP3 deficiency in angiotensin II (Ang II)-induced myocardial remodelling and cardiac dysfunction.
  
  
  RESULTS
  TIMP2(-/-), TIMP3(-/-), and wild-type (WT) mice received Ang II/saline (Alzet pump) for 2 weeks. Ang II infusion resulted in enhanced myocardial hypertrophy and lack of fibrosis in TIMP2(-/-), and conversely, excess fibrosis without hypertrophy in TIMP3(-/-) mice. Echocardiographic imaging revealed preserved ejection fraction in all groups; however, exacerbated left ventricular (LV) diastolic dysfunction was detected in Ang II-infused TIMP2(-/-) and TIMP3(-/-) mice, despite the suppressed Ang II-induced hypertension in TIMP3(-/-) mice. Enhanced hypertrophy in TIMP2(-/-) mice impaired active relaxation, while excess fibrosis in TIMP3(-/-) mice increased LV passive stiffness. Adult WT cardiomyocytes, only when co-cultured with cardiac fibroblasts, exhibited Ang II-induced hypertrophy which was suppressed in TIMP3(-/-) cardiomyocytes. In vitro studies on adult cardiofibroblasts (quiescent and cyclically stretched), and in vivo analyses, revealed that the increased fibrosis in TIMP3(-/-)-Ang II hearts is due to post-translational stabilization and deposition of collagen by matricellular proteins [osteopontin and Secreted Protein Acidic and Rich in Cysteine (SPARC)], which correlated with increased inflammation, rather than increased de novo synthesis. Reduced cross-linking enzymes, LOX and PLOD1, could underlie suppressed collagen deposition in TIMP2(-/-)-Ang II hearts.
  
  
  CONCLUSIONS
  TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function. TIMP2(-/-) and TIMP3(-/-) mice provide a unique opportunity to study myocardial hypertrophy and fibrosis independently, and their impact on cardiac dysfunction.
authors.affiliation: Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute.
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.affiliation: Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Takawale
authors.affiliation: Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: Cardiovascular research Centre, Mazankowski Alberta Heart Institute Department of Medicine/Division of Cardiology, University of Alberta, Edmonton AB, Canada.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kandalam
authors.affiliation: Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cardiovascular research Centre, Mazankowski Alberta Heart Institute Department of Medicine/Division of Cardiology, University of Alberta, Edmonton AB, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: Department of Physiology Cardiovascular research Centre, Mazankowski Alberta Heart Institute z.kassiri@ualberta.ca.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009202:Cardiomyopathies / Q000235:genetics; D005355:Fibrosis / Q000235:genetics; D054144:Heart Failure, Diastolic / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2
keywords: Cardiac fibroblast; Diastolic dysfunction; Extracellular matrix; Fibrosis; Hypertrophy; Matricellular proteins; Tissue inhibitor of metalloproteinase