Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats

DOI Web Site 被引用文献46件
  • Fumitaka Kuwahara
    From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan.
  • Hisashi Kai
    From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan.
  • Keisuke Tokuda
    From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan.
  • Mamiko Kai
    From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan.
  • Akira Takeshita
    From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan.
  • Kensuke Egashira
    From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan.
  • Tsutomu Imaizumi
    From the Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume (F.K., H.K., K.T., T.I.); the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka (M.K.); and Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka (A.T., K.E.), Japan.

抄録

<jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Background</jats:italic> </jats:bold> — </jats:italic> </jats:bold> Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-β in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Methods and Results</jats:italic> </jats:bold> — </jats:italic> </jats:bold> Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-β mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti–TGF-β neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Conclusions</jats:italic> </jats:bold> — </jats:italic> </jats:bold> TGF-β plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts. </jats:p>

収録刊行物

  • Circulation

    Circulation 106 (1), 130-135, 2002-07-02

    Ovid Technologies (Wolters Kluwer Health)

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