Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy

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• 作者：Keiichi Ito^a ; ^{keke-ito@jikei.ac.jp} ; Kenichi Hongo^a ; Taro Date^a ; Masahiro Ikegami^b ; Hiroshi Hano^b ; Mamiko Owada^b ; Satoshi Morimoto^a ; Yusuke Kashiwagi^a ; Daisuke Katoh^a ; Takuya Yoshino^a ; Akira Yoshii^a ; Haruka Kimura^a ; Tomohisa Nagoshi^a ; Ichige Kajimura^c ; Yoichiro Kusakari^c ; Toru Akaike^c ; Susumu Minamisawa^c ; Kazuo Ogawa^a ; Kosuke Minai^a ; Takayuki Ogawa^a ; Makoto Kawai^a ; Junji Yajima^d ; Seiichiro Matsuo^a ; Teiichi Yamane^a ; Ikuo Taniguchi^a ; Sachio Morimoto^e ; Michihiro Yoshimura^a
• 关键词：Thrombin ; Dilated cardiomyopathy ; Direct thrombin inhibitor
• 刊名：International Journal of Cardiology
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：228
• 期：Complete
• 页码：821-827
• 全文大小：1265 K
• 卷排序：228

文摘

Thrombin is a serine protease known to be the final product of the coagulation cascade. However, thrombin plays other physiological roles in processes such as gastric contractions and vessel wound healing, and a state of coagulability is increased in patients with dilated cardiomyopathy (DCM). In this study, we investigate the role of thrombin in the pathogenesis of DCM. The purpose of this study is to clarify the role of thrombin in the pathogenesis of DCM and investigate the possibility of treatment against DCM by thrombin inhibition.MethodsWe investigated the expression of thrombin in the left ventricles of five patients with DCM who underwent the Batista operation and four patients without heart disease. Furthermore, we investigated the involvement of thrombin in the development of DCM using knock-in mice with a deletion mutation of cardiac troponin T that causes human DCM (∆ K210 knock-in mouse) (B6;129-Tnnt2tm2Mmto) and assessed the effects of a direct thrombin inhibitor, dabigatran on ∆ K210 knock-in mice using echocardiographic examinations, the Kaplan-Meier method and Western blotting.ResultsThe immunohistochemical analysis showed a strong thrombin expression in the DCM patients compared to the patients without heart disease. In immunohistochemical analysis, a strong thrombin expression was observed in the heart tissues analysis in the ∆ K210 knock-in mice. Dabigatran administration significantly improved fractional shortening according to the echocardiographic examination and the survival outcomes in ∆ K210 knock-in mice.ConclusionTissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.