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 uncert...
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| Veröffentlicht in: | Laboratory investigation 2005-07, Vol.85 (7), p.862-873 |
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| creator | Ushikoshi, Hiroaki Takahashi, Tomoyuki Chen, Xuehai Khai, Ngin Cin Esaki, Masayasu Goto, Kazuko Takemura, Genzou Maruyama, Rumi Minatoguchi, Shinya Fujiwara, Takako Nagano, Satoshi Yuge, Kentaro Kawai, Takao Murofushi, Yoshiteru Fujiwara, Hisayoshi Kosai, Ken-ichiro |
| description | 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. |
| doi_str_mv | 10.1038/labinvest.3700282 |
| format | Article |
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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.</description><identifier>ISSN: 0023-6837</identifier><identifier>EISSN: 1530-0307</identifier><identifier>DOI: 10.1038/labinvest.3700282</identifier><identifier>PMID: 15856048</identifier><identifier>CODEN: LAINAW</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Animals ; Animals, Newborn ; Antibodies, Monoclonal - pharmacology ; Apoptosis - drug effects ; Apoptosis - physiology ; Biological and medical sciences ; Biotechnology ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Cells, Cultured ; Disease Models, Animal ; Epidermal Growth Factor - biosynthesis ; Epidermal Growth Factor - genetics ; fas Receptor - genetics ; fas Receptor - immunology ; fas Receptor - metabolism ; Fibroblasts - cytology ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Fundamental and applied biological sciences. Psychology ; Genetic Therapy ; Heparin-binding EGF-like Growth Factor ; Hypertrophy, Left Ventricular - genetics ; Hypertrophy, Left Ventricular - metabolism ; Hypertrophy, Left Ventricular - pathology ; Intercellular Signaling Peptides and Proteins ; Investigative techniques, diagnostic techniques (general aspects) ; Laboratory Medicine ; Macrophages - drug effects ; Macrophages - metabolism ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Myocardial Infarction - metabolism ; Myocardial Infarction - pathology ; Myocardial Infarction - therapy ; Myocardial Reperfusion Injury - metabolism ; Myocardial Reperfusion Injury - pathology ; Myocardial Reperfusion Injury - therapy ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Pathology ; Rabbits ; research-article ; Up-Regulation ; Ventricular Remodeling - genetics</subject><ispartof>Laboratory investigation, 2005-07, Vol.85 (7), p.862-873</ispartof><rights>United States and Canadian Academy of Pathology, Inc. 2005</rights><rights>2005 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Jul 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-f64260ab91f1f8cd630583999db962df71c532ff286a9eac0101469429606d1b3</citedby><cites>FETCH-LOGICAL-c508t-f64260ab91f1f8cd630583999db962df71c532ff286a9eac0101469429606d1b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16939795$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15856048$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ushikoshi, Hiroaki</creatorcontrib><creatorcontrib>Takahashi, Tomoyuki</creatorcontrib><creatorcontrib>Chen, Xuehai</creatorcontrib><creatorcontrib>Khai, Ngin Cin</creatorcontrib><creatorcontrib>Esaki, Masayasu</creatorcontrib><creatorcontrib>Goto, Kazuko</creatorcontrib><creatorcontrib>Takemura, Genzou</creatorcontrib><creatorcontrib>Maruyama, Rumi</creatorcontrib><creatorcontrib>Minatoguchi, Shinya</creatorcontrib><creatorcontrib>Fujiwara, Takako</creatorcontrib><creatorcontrib>Nagano, Satoshi</creatorcontrib><creatorcontrib>Yuge, Kentaro</creatorcontrib><creatorcontrib>Kawai, Takao</creatorcontrib><creatorcontrib>Murofushi, Yoshiteru</creatorcontrib><creatorcontrib>Fujiwara, Hisayoshi</creatorcontrib><creatorcontrib>Kosai, Ken-ichiro</creatorcontrib><title>Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes</title><title>Laboratory investigation</title><addtitle>Lab Invest</addtitle><addtitle>Lab Invest</addtitle><description>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.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Disease Models, Animal</subject><subject>Epidermal Growth Factor - biosynthesis</subject><subject>Epidermal Growth Factor - genetics</subject><subject>fas Receptor - genetics</subject><subject>fas Receptor - immunology</subject><subject>fas Receptor - metabolism</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetic Therapy</subject><subject>Heparin-binding EGF-like Growth Factor</subject><subject>Hypertrophy, Left Ventricular - genetics</subject><subject>Hypertrophy, Left Ventricular - metabolism</subject><subject>Hypertrophy, Left Ventricular - pathology</subject><subject>Intercellular Signaling Peptides and Proteins</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Laboratory Medicine</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Myocardial Infarction - metabolism</subject><subject>Myocardial Infarction - pathology</subject><subject>Myocardial Infarction - therapy</subject><subject>Myocardial Reperfusion Injury - metabolism</subject><subject>Myocardial Reperfusion Injury - pathology</subject><subject>Myocardial Reperfusion Injury - therapy</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Pathology</subject><subject>Rabbits</subject><subject>research-article</subject><subject>Up-Regulation</subject><subject>Ventricular Remodeling - genetics</subject><issn>0023-6837</issn><issn>1530-0307</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU1LxDAQhoMouq7-AC9SBL1V89GmyVHF3RUWvOg5pGkilTZZk3bd_fembnFB8DTD5Jl3JvMCcIHgLYKE3TWyrO1ah-6WFBBihg_ABOUEppDA4hBMYo2klJHiBJyG8AEhyjKaH4MTlLOcwoxNQL90SjaJW2uvNyuvQ6idTZxJFg_p03yW6I1U2pey0yHxunWVbmr7nhjXNO5ryNptFPBVHUVqa6RX3SBQbhMZs7XsBsY6-8O4Ad5GqTNwZGQT9PkYp-Bt9vT6uEiXL_Pnx_tlqnLIutTQDFMoS44MMkxVlMCcEc55VXKKK1MglRNsDGZUci0VRPGHlGeYU0grVJIpuNnprrz77OOhRFsHpZtGWu36IGjBM8YwjuDVH_DD9d7G3QTG8bKM4DxCaAcp70Lw2oiVr1vptwJBMRgifg0RoyGx53IU7stWV_uO0YEIXI-ADNEJ46VVddhzlBNe8GE43nEhPtl37fcb_j_9G_ldqIk</recordid><startdate>20050701</startdate><enddate>20050701</enddate><creator>Ushikoshi, Hiroaki</creator><creator>Takahashi, Tomoyuki</creator><creator>Chen, Xuehai</creator><creator>Khai, Ngin Cin</creator><creator>Esaki, Masayasu</creator><creator>Goto, Kazuko</creator><creator>Takemura, Genzou</creator><creator>Maruyama, Rumi</creator><creator>Minatoguchi, Shinya</creator><creator>Fujiwara, Takako</creator><creator>Nagano, Satoshi</creator><creator>Yuge, Kentaro</creator><creator>Kawai, Takao</creator><creator>Murofushi, Yoshiteru</creator><creator>Fujiwara, Hisayoshi</creator><creator>Kosai, Ken-ichiro</creator><general>Nature Publishing Group US</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20050701</creationdate><title>Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes</title><author>Ushikoshi, Hiroaki ; Takahashi, Tomoyuki ; Chen, Xuehai ; Khai, Ngin Cin ; Esaki, Masayasu ; Goto, Kazuko ; Takemura, Genzou ; Maruyama, Rumi ; Minatoguchi, Shinya ; Fujiwara, Takako ; Nagano, Satoshi ; Yuge, Kentaro ; Kawai, Takao ; Murofushi, Yoshiteru ; Fujiwara, Hisayoshi ; Kosai, Ken-ichiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-f64260ab91f1f8cd630583999db962df71c532ff286a9eac0101469429606d1b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Disease Models, Animal</topic><topic>Epidermal Growth Factor - biosynthesis</topic><topic>Epidermal Growth Factor - genetics</topic><topic>fas Receptor - genetics</topic><topic>fas Receptor - immunology</topic><topic>fas Receptor - metabolism</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetic Therapy</topic><topic>Heparin-binding EGF-like Growth Factor</topic><topic>Hypertrophy, Left Ventricular - genetics</topic><topic>Hypertrophy, Left Ventricular - metabolism</topic><topic>Hypertrophy, Left Ventricular - pathology</topic><topic>Intercellular Signaling Peptides and Proteins</topic><topic>Investigative techniques, diagnostic techniques (general aspects)</topic><topic>Laboratory Medicine</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Myocardial Infarction - metabolism</topic><topic>Myocardial Infarction - pathology</topic><topic>Myocardial Infarction - therapy</topic><topic>Myocardial Reperfusion Injury - metabolism</topic><topic>Myocardial Reperfusion Injury - pathology</topic><topic>Myocardial Reperfusion Injury - therapy</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - 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Academic</collection><jtitle>Laboratory investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ushikoshi, Hiroaki</au><au>Takahashi, Tomoyuki</au><au>Chen, Xuehai</au><au>Khai, Ngin Cin</au><au>Esaki, Masayasu</au><au>Goto, Kazuko</au><au>Takemura, Genzou</au><au>Maruyama, Rumi</au><au>Minatoguchi, Shinya</au><au>Fujiwara, Takako</au><au>Nagano, Satoshi</au><au>Yuge, Kentaro</au><au>Kawai, Takao</au><au>Murofushi, Yoshiteru</au><au>Fujiwara, Hisayoshi</au><au>Kosai, Ken-ichiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes</atitle><jtitle>Laboratory investigation</jtitle><stitle>Lab Invest</stitle><addtitle>Lab Invest</addtitle><date>2005-07-01</date><risdate>2005</risdate><volume>85</volume><issue>7</issue><spage>862</spage><epage>873</epage><pages>862-873</pages><issn>0023-6837</issn><eissn>1530-0307</eissn><coden>LAINAW</coden><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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>15856048</pmid><doi>10.1038/labinvest.3700282</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0023-6837 |
| ispartof | Laboratory investigation, 2005-07, Vol.85 (7), p.862-873 |
| issn | 0023-6837 1530-0307 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67948822 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Animals, Newborn Antibodies, Monoclonal - pharmacology Apoptosis - drug effects Apoptosis - physiology Biological and medical sciences Biotechnology Cell Proliferation - drug effects Cell Survival - drug effects Cells, Cultured Disease Models, Animal Epidermal Growth Factor - biosynthesis Epidermal Growth Factor - genetics fas Receptor - genetics fas Receptor - immunology fas Receptor - metabolism Fibroblasts - cytology Fibroblasts - drug effects Fibroblasts - metabolism Fundamental and applied biological sciences. Psychology Genetic Therapy Heparin-binding EGF-like Growth Factor Hypertrophy, Left Ventricular - genetics Hypertrophy, Left Ventricular - metabolism Hypertrophy, Left Ventricular - pathology Intercellular Signaling Peptides and Proteins Investigative techniques, diagnostic techniques (general aspects) Laboratory Medicine Macrophages - drug effects Macrophages - metabolism Male Medical sciences Medicine Medicine & Public Health Mice Myocardial Infarction - metabolism Myocardial Infarction - pathology Myocardial Infarction - therapy Myocardial Reperfusion Injury - metabolism Myocardial Reperfusion Injury - pathology Myocardial Reperfusion Injury - therapy Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Pathology Rabbits research-article Up-Regulation Ventricular Remodeling - genetics |
| title | Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T21%3A08%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Local%20overexpression%20of%20HB-EGF%20exacerbates%20remodeling%20following%20myocardial%20infarction%20by%20activating%20noncardiomyocytes&rft.jtitle=Laboratory%20investigation&rft.au=Ushikoshi,%20Hiroaki&rft.date=2005-07-01&rft.volume=85&rft.issue=7&rft.spage=862&rft.epage=873&rft.pages=862-873&rft.issn=0023-6837&rft.eissn=1530-0307&rft.coden=LAINAW&rft_id=info:doi/10.1038/labinvest.3700282&rft_dat=%3Cproquest_cross%3E971792791%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=220288325&rft_id=info:pmid/15856048&rfr_iscdi=true |