TY - JOUR
T1 - Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy
AU - Ito, Keiichi
AU - Hongo, Kenichi
AU - Date, Taro
AU - Ikegami, Masahiro
AU - Hano, Hiroshi
AU - Owada, Mamiko
AU - Morimoto, Satoshi
AU - Kashiwagi, Yusuke
AU - Katoh, Daisuke
AU - Yoshino, Takuya
AU - Yoshii, Akira
AU - Kimura, Haruka
AU - Nagoshi, Tomohisa
AU - Kajimura, Ichige
AU - Kusakari, Yoichiro
AU - Akaike, Toru
AU - Minamisawa, Susumu
AU - Ogawa, Kazuo
AU - Minai, Kosuke
AU - Ogawa, Takayuki
AU - Kawai, Makoto
AU - Yajima, Junji
AU - Matsuo, Seiichiro
AU - Yamane, Teiichi
AU - Taniguchi, Ikuo
AU - Morimoto, Sachio
AU - Yoshimura, Michihiro
N1 - Funding Information:
The present study was supported by JSPS KAKENHI Grant Number 26860589 , the Uehara Memorial Foundation and The Jikei University Research Fund .
Publisher Copyright:
© 2016 Elsevier Ireland Ltd
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Background 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. Methods We 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-Tnnt2 tm2Mmto) 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. Results The 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. Conclusion Tissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.
AB - Background 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. Methods We 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-Tnnt2 tm2Mmto) 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. Results The 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. Conclusion Tissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.
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U2 - 10.1016/j.ijcard.2016.11.176
DO - 10.1016/j.ijcard.2016.11.176
M3 - Article
C2 - 27888761
AN - SCOPUS:84996774852
SN - 0167-5273
VL - 228
SP - 821
EP - 827
JO - International Journal of Cardiology
JF - International Journal of Cardiology
ER -
