Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes.
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.
Ushikoshi
Hiroaki
H
Department of Gene Therapy and Regenerative Medicine, Gifu University School of Medicine, Gifu, Japan.
Takahashi
Tomoyuki
T
Chen
Xuehai
X
Khai
Ngin Cin
NC
Esaki
Masayasu
M
Goto
Kazuko
K
Takemura
Genzou
G
Maruyama
Rumi
R
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Nagano
Satoshi
S
Yuge
Kentaro
K
Kawai
Takao
T
Murofushi
Yoshiteru
Y
Fujiwara
Hisayoshi
H
Kosai
Ken-ichiro
K
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
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