Published online before print March 17, 2005, doi: 10.1161/01.RES.0000163016.52653.2e
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Submitted on October 4, 2004
Revised on February 28, 2005
Accepted on March 7, 2005
Hepatocyte Growth Factor Ameliorates the Progression of Experimental Autoimmune Myocarditis. A Potential Role for Induction of T Helper 2 Cytokines
Hideki Futamatsu ;
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
* To whom correspondence should be addressed. 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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