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The <jats:styled-content style=\"fixed-case\">TWEAK<\/jats:styled-content>\/Fn14 axis is a positive regulator of cardiac hypertrophy in cardiomyopathy. This study therefore investigated the effects of Fn14 on atrial hypertrophy and underlying cellular mechanisms using <jats:styled-content style=\"fixed-case\">HL<\/jats:styled-content>\u20101 atrial myocytes. In patients with <jats:styled-content style=\"fixed-case\">AF<\/jats:styled-content>, Fn14 protein levels were higher in atrial myocytes from atrial appendages, and expression of <jats:styled-content style=\"fixed-case\">TWEAK<\/jats:styled-content> was increased in peripheral blood mononuclear cells, while <jats:styled-content style=\"fixed-case\">TWEAK<\/jats:styled-content> serum levels were decreased. In vitro, Fn14 expression was up\u2010regulated in response to <jats:styled-content style=\"fixed-case\">TWEAK<\/jats:styled-content> treatment in <jats:styled-content style=\"fixed-case\">HL<\/jats:styled-content>\u20101 atrial myocytes. <jats:styled-content style=\"fixed-case\">TWEAK<\/jats:styled-content> increased the expression of <jats:styled-content style=\"fixed-case\">ANP<\/jats:styled-content> and Troponin T, and Fn14 knockdown counteracted the effect. Inhibition of <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>2, <jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>3 by specific si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> attenuated <jats:styled-content style=\"fixed-case\">TWEAK<\/jats:styled-content>\u2010induced <jats:styled-content style=\"fixed-case\">HL<\/jats:styled-content>\u20101 atrial myocytes hypertrophy. 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