title: Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy.
abstract: 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 ip). Two weeks later, when cardiac dysfunction was apparent, an adenoviral vector encoding human HGF gene (Ad.CAG-HGF, 1x10(11) particles/mouse) was injected into the hindlimb muscles; LacZ gene served as the control. Left ventricular dilatation and dysfunction normally seen 4 wk 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 the expression of both was restored by HGF treatment. The protective effect of HGF against doxorubicin-induced cardiomyocyte atrophy was confirmed in an in vitro experiment, which also showed that neither cardiomyocyte apoptosis nor proliferation plays 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, the activation of extracellular signal-regulated kinase (ERK) was reduced by doxorubicin, but the activity was restored by HGF. Levels of transforming growth factor-beta1 and cyclooxygenase-2 did not differ between the groups. Our findings suggest the HGF gene delivery exerts therapeutic antiatrophic/degenerative and antifibrotic 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.
authors: Division of Cardiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors: Masayasu
authors: M
authors: Esaki
authors: Genzou
authors: G
authors: Takemura
authors: Ken-ichiro
authors: K
authors: Kosai
authors: Tomoyuki
authors: T
authors: Takahashi
authors: Shusaku
authors: S
authors: Miyata
authors: Longhu
authors: L
authors: Li
authors: Kazuko
authors: K
authors: Goto
authors: Rumi
authors: R
authors: Maruyama
authors: Hideshi
authors: H
authors: Okada
authors: Hiromitsu
authors: H
authors: Kanamori
authors: Atsushi
authors: A
authors: Ogino
authors: Hiroaki
authors: H
authors: Ushikoshi
authors: Shinya
authors: S
authors: Minatoguchi
authors: Takako
authors: T
authors: Fujiwara
authors: Hisayoshi
authors: H
authors: Fujiwara
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000502:physiology; D005822:Genetic Vectors; D006321:Heart / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D050991:GATA4 Transcription Factor; D017228:Hepatocyte Growth Factor; D004317:Doxorubicin; D051546:Cyclooxygenase 2; D019859:Proto-Oncogene Proteins c-met; D048049:Extracellular Signal-Regulated MAP Kinases