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(Circulation Research. 2005;96:823.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Hepatocyte Growth Factor Ameliorates the Progression of Experimental Autoimmune Myocarditis

A Potential Role for Induction of T Helper 2 Cytokines

Hideki Futamatsu, Jun-ichi Suzuki, Shinya Mizuno, Noritaka Koga, Susumu Adachi, Hisanori Kosuge, Yasuhiro Maejima, Kenzo Hirao, Toshikazu Nakamura, Mitsuaki Isobe

From the Department of Cardiovascular Medicine (H.F., J.S., N.K., S.A., H.K., Y.M., K.H., M.I.), Tokyo Medical and Dental University, Tokyo, Japan; and the Division of Molecular Regenerative Medicine, Department of Molecular Regenerative Medicine (S.M., T.N.), Osaka University Graduate School of Medicine, Osaka, Japan

Correspondence to Mitsuaki Isobe, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail isobemi.cvm{at}tmd.ac.jp

Hepatocyte growth factor (HGF) plays a role in cell protection, antiapoptosis, antifibrosis, and angiogenesis. However, the role of HGF in the immune system is not well defined. We examined the influence of HGF on T cells and the effects of HGF therapy in acute myocarditis. Lewis rats were immunized on day 0 with cardiac myosin to establish experimental autoimmune myocarditis (EAM). Human HGF gene with hemagglutinating virus of the Japan-envelope vector was injected directly into the myocardium on day 0 or on day 14 (two groups of treated rats). Rats were killed on day 21. Expression of c-Met/HGF receptor in splenocytes and myocardial infiltrating cells was confirmed by immunohistochemical staining or FACS analysis. Myocarditis-affected areas were smaller in the treated rats than in control rats. Cardiac function in the treated rats was markedly improved. An antigen-specific T cell proliferation assay was done with CD4-positive T cells isolated from control rats stimulated with cardiac myosin. HGF suppressed T cell proliferation and production of IFN- and increased production of IL-4 and IL-10 secreted from CD4-positive T cells in vitro. Additionally, TUNEL assay revealed that HGF reduced apoptosis in cardiomyocytes. HGF reduced the severity of EAM by inducing T helper 2 cytokines and suppressing apoptosis of cardiomyocytes. HGF has potential as a new therapy for myocarditis.

Key Words: hepatocyte growth factor • myocarditis • Th1/Th2 cytokines • gene therapy • immune system

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