Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes

Autor: Xue-Hai Chen, Kentaro Yuge, Tomoyuki Takahashi, Rumi Maruyama, Hiroaki Ushikoshi, Ngin Cin Khai, Shinya Minatoguchi, Kazuko Goto, Takao Kawai, Takako Fujiwara, Satoshi Nagano, Masayasu Esaki, Genzou Takemura, Ken-ichiro Kosai, Hisayoshi Fujiwara, Yoshiteru Murofushi
Rok vydání: 2005
Předmět:
Male
medicine.medical_specialty
Cell Survival
Heparin-binding EGF-like growth factor
medicine.medical_treatment
Myocardial Infarction
Apoptosis
Myocardial Reperfusion Injury
Pathology and Forensic Medicine
Muscle hypertrophy
Mice
Epidermal growth factor
Fibrosis
Internal medicine
medicine
Animals
Myocytes
Cardiac
fas Receptor
Ventricular remodeling
Molecular Biology
Cells
Cultured
Cell Proliferation
Epidermal Growth Factor
Ventricular Remodeling
business.industry
Macrophages
Growth factor
Genetic transfer
Antibodies
Monoclonal
Genetic Therapy
Cell Biology
Fibroblasts
medicine.disease
Up-Regulation
Disease Models
Animal
Endocrinology
Animals
Newborn
Intercellular Signaling Peptides and Proteins
Hypertrophy
Left Ventricular
Hepatocyte growth factor
Rabbits
business
Heparin-binding EGF-like Growth Factor
medicine.drug
Zdroj: Laboratory Investigation. 85:862-873
ISSN: 0023-6837
DOI: 10.1038/labinvest.3700282
Popis: Insulin-like growth factor (IGF), hepatocyte growth factor (HGF), and heparin-binding epidermal growth factor-like growth factor (HB-EGF) are cardiogenic and cardiohypertrophic growth factors. Although the therapeutic effects of IGF and HGF have been well demonstrated in injured hearts, it is uncertain whether natural upregulation of HB-EGF after myocardial infarction (MI) plays a beneficial or pathological role in the process of remodeling. To answer this question, we conducted adenoviral HB-EGF gene transduction in in vitro and in vivo injured heart models, allowing us to highlight and explore the HB-EGF-induced phenotypes. Overexpressed HB-EGF had no cytoprotective or additive death-inducible effect on Fas-induced apoptosis or oxidative stress injury in primary cultured mouse cardiomyocytes, although it significantly induced hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. Locally overexpressed HB-EGF in the MI border area in rabbit hearts did not improve cardiac function or exhibit an angiogenic effect, and instead exacerbated remodeling at the subacute and chronic stages post-MI. Namely, it elevated the levels of apoptosis, fibrosis, and the accumulation of myofibroblasts and macrophages in the MI area, in addition to inducing left ventricular hypertrophy. Thus, upregulated HB-EGF plays a pathophysiological role in injured hearts in contrast to the therapeutic roles of IGF and HGF. These results imply that regulation of HB-EGF may be a therapeutic target for treating cardiac hypertrophy and fibrosis.
Databáze: OpenAIRE
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