title: Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes.
abstract: 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.
authors.affiliation: Department of Gene Therapy and Regenerative Medicine, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushikoshi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Xuehai
authors.initials: X
authors.lastname: Chen
authors.forename: Ngin Cin
authors.initials: NC
authors.lastname: Khai
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagano
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yuge
authors.forename: Takao
authors.initials: T
authors.lastname: Kawai
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Murofushi
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kosai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015316:Genetic Therapy; D066257:Heparin-binding EGF-like Growth Factor; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D019014:fas Receptor; D004815:Epidermal Growth Factor