title: Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63-Integrin β1 Interaction.
abstract: Myocardial fibrosis is excess accumulation of the extracellular matrix fibrillar collagens. Fibrosis is a key feature of various cardiomyopathies and compromises cardiac systolic and diastolic performance. TIMP1 (tissue inhibitor of metalloproteinase-1) is consistently upregulated in myocardial fibrosis and is used as a marker of fibrosis. However, it remains to be determined whether TIMP1 promotes tissue fibrosis by inhibiting extracellular matrix degradation by matrix metalloproteinases or via an matrix metalloproteinase-independent pathway. We examined the function of TIMP1 in myocardial fibrosis usingTimp1-deficient mice and 2 in vivo models of myocardial fibrosis (angiotensin II infusion and cardiac pressure overload), in vitro analysis of adult cardiac fibroblasts, and fibrotic myocardium from patients with dilated cardiomyopathy (DCM).Timp1deficiency significantly reduced myocardial fibrosis in both in vivo models of cardiomyopathy. We identified a novel mechanism for TIMP1 action whereby, independent from its matrix metalloproteinase-inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2/3 and β-catenin, leading to de novo collagen synthesis. This mechanism was consistently observed in vivo, in cultured cardiac fibroblasts, and in human fibrotic myocardium. In addition, after long-term pressure overload,Timp1deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase-independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies.
authors.affiliation: From the Department of Physiology (A.T., P.Z., X.W., G.O., Z.K.), Department of Medicine/Division of Cardiology (V.B.P., G.O.), and Cardiovascular Research Center, Mazankowski Alberta Heart Institute (A.T., P.Z., V.B.P., X.W., G.O., Z.K.), University of Alberta, Edmonton, Canada.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Takawale
authors.affiliation: From the Department of Physiology (A.T., P.Z., X.W., G.O., Z.K.), Department of Medicine/Division of Cardiology (V.B.P., G.O.), and Cardiovascular Research Center, Mazankowski Alberta Heart Institute (A.T., P.Z., V.B.P., X.W., G.O., Z.K.), University of Alberta, Edmonton, Canada.
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: From the Department of Physiology (A.T., P.Z., X.W., G.O., Z.K.), Department of Medicine/Division of Cardiology (V.B.P., G.O.), and Cardiovascular Research Center, Mazankowski Alberta Heart Institute (A.T., P.Z., V.B.P., X.W., G.O., Z.K.), University of Alberta, Edmonton, Canada.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: From the Department of Physiology (A.T., P.Z., X.W., G.O., Z.K.), Department of Medicine/Division of Cardiology (V.B.P., G.O.), and Cardiovascular Research Center, Mazankowski Alberta Heart Institute (A.T., P.Z., V.B.P., X.W., G.O., Z.K.), University of Alberta, Edmonton, Canada.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Physiology (A.T., P.Z., X.W., G.O., Z.K.), Department of Medicine/Division of Cardiology (V.B.P., G.O.), and Cardiovascular Research Center, Mazankowski Alberta Heart Institute (A.T., P.Z., V.B.P., X.W., G.O., Z.K.), University of Alberta, Edmonton, Canada.
authors.forename: Gavin
authors.initials: G
authors.lastname: Oudit
authors.affiliation: From the Department of Physiology (A.T., P.Z., X.W., G.O., Z.K.), Department of Medicine/Division of Cardiology (V.B.P., G.O.), and Cardiovascular Research Center, Mazankowski Alberta Heart Institute (A.T., P.Z., V.B.P., X.W., G.O., Z.K.), University of Alberta, Edmonton, Canada. z.kassiri@ualberta.ca.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D060149:Tetraspanin 30 / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114243:Itgb1bp1 protein, mouse; D009419:Nerve Tissue Proteins; D060149:Tetraspanin 30; D019715:Tissue Inhibitor of Metalloproteinase-1; D000804:Angiotensin II; D012313:RNA; D020781:Matrix Metalloproteinase 1
keywords: CD63; extracellular matrix; fibrosis; heart failure; integrins; matrix metalloproteinases