Submitted on September 22, 2007
Accepted on December 7, 2007
Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy
Masayasu Esaki1, Genzou Takemura1*, Ken-ichiro Kosai2, Tomoyuki Takahashi2, Shusaku Miyata1, Longhu Li1, Kazuko Goto1, Rumi Maruyama3, Hideshi Okada1, Hiromitsu Kanamori3, Atsushi Ogino3, Hiroaki Ushikoshi3, Shinya Minatoguchi3, Takako Fujiwara4, and Hisayoshi Fujiwara3
1 Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
2 Div. of Gene Therapy and Regenerative Medicine, Kurume Univ., Kurume, Japan
3 Gifu, Japan; Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
4 Department of Food Science, Kyoto Women's University, Kyoto, Japan
* To whom correspondence should be addressed. E-mail: gt{at}gifu-u.ac.jp.
Hepatocyte growth factor (HGF) reportedly exerts beneficial effects on the heart following myocardial infarction and during nonischemic cardiomyopathy, but the precise mechanisms underlying the latter have not been well elucidated. We generated nonischemic cardiomyopathy in mice by injecting them with doxorubicin (15 mg/kg i.p.). Two weeks later, when cardiac dysfunction was apparent, an adenoviral vector encoding human HGF gene (Ad.CAG-HGF, 1x1011 particles/mouse) was injected into the hindlimb muscles; LacZ gene served as the control. Left ventricular dilatation and dysfunction normally seen 4 weeks after doxorubicin administration were significantly mitigated in HGF-treated mice, as were the associated cardiomyocyte atrophy/degeneration and myocardial fibrosis. Myocardial expression of GATA-4 and a sarcomeric protein, myosin heavy chain, was downregulated by doxorubicin, but expression of both was restored by HGF treatment. The protective effect HGF against doxorubicin-induced cardiomyocyte atrophy was confirmed in an in vitro experiment, which also showed that neither cardiomyocyte apoptosis nor proliferation play significant roles in the present model. Upregulation of c-Met/HGF receptor was noted in HGF-treated hearts. Among the mediators downstream of c-Met, activation of extracellular signal-regulated kinase (ERK) was reduced by doxorubicin, but the activity was restored by HGF. Levels of transforming growth factor-
1 and cyclooxygenase-2 did not differ between the groups. Our findings suggest HGF gene deliver exerts therapeutic anti-atrophic/degenerative and anti-fibrotic effects on myocardium in cases of established cardiac dysfunction caused by doxorubicin. These beneficial effects appear to be related to HGF-induced ERK activation and upregulation of c-Met, GATA-4 and sarcomeric proteins.
