Disruption of actin dynamics regulated by Rho effector mDia1 attenuates pressure overload-induced cardiac hypertrophic responses and exacerbates dysfunction

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  • Ichitaro Abe
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Takeshi Terabayashi
    Department of Pharmacology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Katsuhiro Hanada
    Clinical Engineering Research Center, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, Japan
  • Hidekazu Kondo
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Yasushi Teshima
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Yumi Ishii
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Miho Miyoshi
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Shintaro Kira
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Shotaro Saito
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Hirotsugu Tsuchimochi
    Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka, Japan
  • Mikiyasu Shirai
    Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka, Japan
  • Kunio Yufu
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Motoki Arakane
    Department of Diagnostic Pathology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, Japan
  • Tsutomu Daa
    Department of Diagnostic Pathology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita, Japan
  • Dean Thumkeo
    Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan
  • Shuh Narumiya
    Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan
  • Naohiko Takahashi
    Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan
  • Toshimasa Ishizaki
    Department of Pharmacology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan

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<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload and that Rho signalling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a Rho-effector molecule, in pressure overload-induced ventricular hypertrophy.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results </jats:title> <jats:p>Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10–12 weeks old) were subjected to a transverse aortic constriction (TAC) or sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy-related genes, including immediate early genes, in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the filamentous/globular (F/G)-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors and serum response factor were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion </jats:title> <jats:p>mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.</jats:p> </jats:sec>

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