{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T16:49:48Z","timestamp":1794242988106,"version":"4.9.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Hypertension"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>\n            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\u2013independent pathway. We examined the function of TIMP1 in myocardial fibrosis using\n            <jats:italic>Timp1<\/jats:italic>\n            -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).\n            <jats:italic>Timp1<\/jats:italic>\n            deficiency 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\u2013inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin \u03b21 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2\/3 and \u03b2-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,\n            <jats:italic>Timp1<\/jats:italic>\n            deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase\u2013independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies.\n          <\/jats:p>","DOI":"10.1161\/hypertensionaha.117.09045","type":"journal-article","created":{"date-parts":[[2017,4,4]],"date-time":"2017-04-04T01:00:28Z","timestamp":1491267628000},"page":"1092-1103","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":179,"title":["Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63\u2013Integrin \u03b21 Interaction"],"prefix":"10.1161","volume":"69","author":[{"given":"Abhijit","family":"Takawale","sequence":"first","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Zhang","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav B.","family":"Patel","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhua","family":"Wang","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Oudit","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zamaneh","family":"Kassiri","sequence":"additional","affiliation":[{"name":"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, 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ensionaha.117.09045","relation":{},"ISSN":["0194-911X","1524-4563"],"issn-type":[{"value":"0194-911X","type":"print"},{"value":"1524-4563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6]]},"assertion":[{"value":"2017-01-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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