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: Hiroaki Ushikoshi, Tomoyuki Takahashi, Xuehai Chen, Ngin Cin Khai, Masayasu Esaki, Kazuko Goto, Genzou Takemura, Rumi Maruyama, Shinya Minatoguchi, Takako Fujiwara, Satoshi Nagano, Kentaro Yuge, Takao Kawai, Yoshiteru Murofushi, Hisayoshi Fujiwara, Ken-ichiro Kosai
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 85 Issue 7 Pg. 862-73 (Jul 2005) ISSN: 0023-6837 [Print] United States
• PMID: 15856048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Hbegf protein, mouse
• Heparin-binding EGF-like Growth Factor
• Intercellular Signaling Peptides and Proteins
• fas Receptor
• Epidermal Growth Factor

Topics

• Animals
• Animals, Newborn
• Antibodies, Monoclonal (pharmacology)
• Apoptosis (drug effects, physiology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Epidermal Growth Factor (biosynthesis, genetics)
• Fibroblasts (cytology, drug effects, metabolism)
• Genetic Therapy
• Heparin-binding EGF-like Growth Factor
• Hypertrophy, Left Ventricular (genetics, metabolism, pathology)
• Intercellular Signaling Peptides and Proteins
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Myocardial Infarction (metabolism, pathology, therapy)
• Myocardial Reperfusion Injury (metabolism, pathology, therapy)
• Myocytes, Cardiac (drug effects, metabolism)
• Rabbits
• Up-Regulation
• Ventricular Remodeling (genetics)
• fas Receptor (genetics, immunology, metabolism)