Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart
Background Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide produced in the heart, but controversy persists regarding its cardiac effects. We explored the potential role of AM on cardiac function and remodeling by direct recombinant adenoviral AM gene delivery into the anterior wa...
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| Veröffentlicht in: | The journal of gene medicine 2008-08, Vol.10 (8), p.867-877 |
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| creator | Leskinen, Hanna Rauma-Pinola, Tanja Szokodi, István Kerkelä, Risto Pikkarainen, Sampsa Uusimaa, Paavo Hautala, Timo Vuolteenaho, Olli Ruskoaho, Heikki |
| description | Background
Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide produced in the heart, but controversy persists regarding its cardiac effects. We explored the potential role of AM on cardiac function and remodeling by direct recombinant adenoviral AM gene delivery into the anterior wall of the left ventricle (LV).
Methods
AM was overexpressed in healthy rat hearts and in hearts during the remodeling process in response to pressure overload and myocardial infarction. The AM effects were analysed with echocardiography and in an isolated perfused rat heart preparation. The expression of AM and the activation of underlying signaling pathways were also investigated.
Results
AM mRNA increased by 20.9‐fold (p < 0.001) in healthy rat heart and improved fractional shortening by 14% (p < 0.05) and ejection fraction by 8% (p < 0.05). In isolated perfused hearts, an increase (p < 0.05) in the first derivative of isovolumic LV pressure rise (dP/dtmax) without alteration in diastolic properties was noted. The overexpression of AM activated protein kinase Cε and Cδ isoforms in the LV, whereas p38 mitogen‐activated protein kinase activity decreased. Angiotensin II‐induced LV hypertrophy was significantly attenuated by AM (p < 0.01) without compromising cardiac contractility. By contrast, AM enhanced LV dilatation (p < 0.01) and anterior wall thinning (p < 0.001) and augmented the deterioration of LV function (p < 0.05) post‐infarction.
Conclusions
The results obtained in the present study show that AM overexpression improves LV systolic function without altering cardiac diastolic properties in the normal heart. Moreover, AM is a potent context‐dependent modulator of LV remodeling because it promotes an adaptive response in pressure overload‐induced LV hypertrophy and triggers a maladaptive process in post‐infarction remodeling. Copyright © 2008 John Wiley & Sons, Ltd. |
| doi_str_mv | 10.1002/jgm.1219 |
| format | Article |
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Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide produced in the heart, but controversy persists regarding its cardiac effects. We explored the potential role of AM on cardiac function and remodeling by direct recombinant adenoviral AM gene delivery into the anterior wall of the left ventricle (LV).
Methods
AM was overexpressed in healthy rat hearts and in hearts during the remodeling process in response to pressure overload and myocardial infarction. The AM effects were analysed with echocardiography and in an isolated perfused rat heart preparation. The expression of AM and the activation of underlying signaling pathways were also investigated.
Results
AM mRNA increased by 20.9‐fold (p < 0.001) in healthy rat heart and improved fractional shortening by 14% (p < 0.05) and ejection fraction by 8% (p < 0.05). In isolated perfused hearts, an increase (p < 0.05) in the first derivative of isovolumic LV pressure rise (dP/dtmax) without alteration in diastolic properties was noted. The overexpression of AM activated protein kinase Cε and Cδ isoforms in the LV, whereas p38 mitogen‐activated protein kinase activity decreased. Angiotensin II‐induced LV hypertrophy was significantly attenuated by AM (p < 0.01) without compromising cardiac contractility. By contrast, AM enhanced LV dilatation (p < 0.01) and anterior wall thinning (p < 0.001) and augmented the deterioration of LV function (p < 0.05) post‐infarction.
Conclusions
The results obtained in the present study show that AM overexpression improves LV systolic function without altering cardiac diastolic properties in the normal heart. Moreover, AM is a potent context‐dependent modulator of LV remodeling because it promotes an adaptive response in pressure overload‐induced LV hypertrophy and triggers a maladaptive process in post‐infarction remodeling. Copyright © 2008 John Wiley & Sons, Ltd.]]></description><identifier>ISSN: 1099-498X</identifier><identifier>EISSN: 1521-2254</identifier><identifier>DOI: 10.1002/jgm.1219</identifier><identifier>PMID: 18615773</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Adenoviridae - drug effects ; Adrenomedullin - metabolism ; Adrenomedullin - pharmacology ; Animals ; Gene therapy ; gene transfer ; Gene Transfer Techniques ; Heart - drug effects ; Heart - physiology ; Heart - physiopathology ; Heart Ventricles - drug effects ; hypertrophy ; Hypertrophy, Left Ventricular - metabolism ; Hypertrophy, Left Ventricular - physiopathology ; left ventricular remodeling ; Male ; myocardial infarction ; Myocardial Infarction - physiopathology ; Myocardium - metabolism ; Rats ; Rats, Sprague-Dawley ; RNA, Messenger - metabolism ; Systole - drug effects ; systolic function ; Ventricular Function, Left - drug effects</subject><ispartof>The journal of gene medicine, 2008-08, Vol.10 (8), p.867-877</ispartof><rights>Copyright © 2008 John Wiley & Sons, Ltd.</rights><rights>(c) 2008 John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4519-50d3c25996b8c3b21c06ef902cca8ccc822804811259948ab8e6ed71bb3857eb3</citedby><cites>FETCH-LOGICAL-c4519-50d3c25996b8c3b21c06ef902cca8ccc822804811259948ab8e6ed71bb3857eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjgm.1219$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjgm.1219$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18615773$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leskinen, Hanna</creatorcontrib><creatorcontrib>Rauma-Pinola, Tanja</creatorcontrib><creatorcontrib>Szokodi, István</creatorcontrib><creatorcontrib>Kerkelä, Risto</creatorcontrib><creatorcontrib>Pikkarainen, Sampsa</creatorcontrib><creatorcontrib>Uusimaa, Paavo</creatorcontrib><creatorcontrib>Hautala, Timo</creatorcontrib><creatorcontrib>Vuolteenaho, Olli</creatorcontrib><creatorcontrib>Ruskoaho, Heikki</creatorcontrib><title>Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart</title><title>The journal of gene medicine</title><addtitle>J. Gene Med</addtitle><description><![CDATA[Background
Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide produced in the heart, but controversy persists regarding its cardiac effects. We explored the potential role of AM on cardiac function and remodeling by direct recombinant adenoviral AM gene delivery into the anterior wall of the left ventricle (LV).
Methods
AM was overexpressed in healthy rat hearts and in hearts during the remodeling process in response to pressure overload and myocardial infarction. The AM effects were analysed with echocardiography and in an isolated perfused rat heart preparation. The expression of AM and the activation of underlying signaling pathways were also investigated.
Results
AM mRNA increased by 20.9‐fold (p < 0.001) in healthy rat heart and improved fractional shortening by 14% (p < 0.05) and ejection fraction by 8% (p < 0.05). In isolated perfused hearts, an increase (p < 0.05) in the first derivative of isovolumic LV pressure rise (dP/dtmax) without alteration in diastolic properties was noted. The overexpression of AM activated protein kinase Cε and Cδ isoforms in the LV, whereas p38 mitogen‐activated protein kinase activity decreased. Angiotensin II‐induced LV hypertrophy was significantly attenuated by AM (p < 0.01) without compromising cardiac contractility. By contrast, AM enhanced LV dilatation (p < 0.01) and anterior wall thinning (p < 0.001) and augmented the deterioration of LV function (p < 0.05) post‐infarction.
Conclusions
The results obtained in the present study show that AM overexpression improves LV systolic function without altering cardiac diastolic properties in the normal heart. Moreover, AM is a potent context‐dependent modulator of LV remodeling because it promotes an adaptive response in pressure overload‐induced LV hypertrophy and triggers a maladaptive process in post‐infarction remodeling. Copyright © 2008 John Wiley & Sons, Ltd.]]></description><subject>Adenoviridae - drug effects</subject><subject>Adrenomedullin - metabolism</subject><subject>Adrenomedullin - pharmacology</subject><subject>Animals</subject><subject>Gene therapy</subject><subject>gene transfer</subject><subject>Gene Transfer Techniques</subject><subject>Heart - drug effects</subject><subject>Heart - physiology</subject><subject>Heart - physiopathology</subject><subject>Heart Ventricles - drug effects</subject><subject>hypertrophy</subject><subject>Hypertrophy, Left Ventricular - metabolism</subject><subject>Hypertrophy, Left Ventricular - physiopathology</subject><subject>left ventricular remodeling</subject><subject>Male</subject><subject>myocardial infarction</subject><subject>Myocardial Infarction - physiopathology</subject><subject>Myocardium - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>RNA, Messenger - metabolism</subject><subject>Systole - drug effects</subject><subject>systolic function</subject><subject>Ventricular Function, Left - drug effects</subject><issn>1099-498X</issn><issn>1521-2254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp10VtrFDEYBuAgFXtQ8BdIoCC9mZrDZJJctqVdlfVwoVV6EzKZb9vZziRjMtPDvzfLjgoFr_IFnryE70XoNSXHlBD2bn3dH1NG9TO0RwWjBWOi3Mkz0bootfq5i_ZTWhNCpVL6BdqlqqJCSr6H-pPGDmN7BzhE3NvO_rlGSEPwCfAYsG3Ah7s22i6PMc89NFPXtR5fg88iWp9WEHGbsAt-hIexaGAAn5-NOKvxBvAN2Di-RM9Xtkvwaj4P0PeL829n74vll8WHs5Nl4UpBdSFIwx0TWle1crxm1JEKVpow56xyzinGFCkVpRtTKlsrqKCRtK65EhJqfoDebnOHGH5NkEbTt8lB11kPYUqm0lzIipcZHj6B6zBFn_9mqMxEa01EVkdb5WJIKcLKDLHtbXw0lJhNASYXYDYFZPpmDpzqvKV_cN54BsUW3LcdPP43yHxcfJoDZ9-mvNi_3sZbU0kuhfnxeWEur5ZXX08vKyP4b-wYn1U</recordid><startdate>200808</startdate><enddate>200808</enddate><creator>Leskinen, Hanna</creator><creator>Rauma-Pinola, Tanja</creator><creator>Szokodi, István</creator><creator>Kerkelä, Risto</creator><creator>Pikkarainen, Sampsa</creator><creator>Uusimaa, Paavo</creator><creator>Hautala, Timo</creator><creator>Vuolteenaho, Olli</creator><creator>Ruskoaho, Heikki</creator><general>John Wiley & Sons, Ltd</general><general>Wiley Periodicals Inc</general><scope>BSCLL</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>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>200808</creationdate><title>Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart</title><author>Leskinen, Hanna ; Rauma-Pinola, Tanja ; Szokodi, István ; Kerkelä, Risto ; Pikkarainen, Sampsa ; Uusimaa, Paavo ; Hautala, Timo ; Vuolteenaho, Olli ; Ruskoaho, Heikki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4519-50d3c25996b8c3b21c06ef902cca8ccc822804811259948ab8e6ed71bb3857eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adenoviridae - drug effects</topic><topic>Adrenomedullin - metabolism</topic><topic>Adrenomedullin - pharmacology</topic><topic>Animals</topic><topic>Gene therapy</topic><topic>gene transfer</topic><topic>Gene Transfer Techniques</topic><topic>Heart - drug effects</topic><topic>Heart - physiology</topic><topic>Heart - physiopathology</topic><topic>Heart Ventricles - drug effects</topic><topic>hypertrophy</topic><topic>Hypertrophy, Left Ventricular - metabolism</topic><topic>Hypertrophy, Left Ventricular - physiopathology</topic><topic>left ventricular remodeling</topic><topic>Male</topic><topic>myocardial infarction</topic><topic>Myocardial Infarction - physiopathology</topic><topic>Myocardium - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>RNA, Messenger - metabolism</topic><topic>Systole - drug effects</topic><topic>systolic function</topic><topic>Ventricular Function, Left - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Leskinen, Hanna</creatorcontrib><creatorcontrib>Rauma-Pinola, Tanja</creatorcontrib><creatorcontrib>Szokodi, István</creatorcontrib><creatorcontrib>Kerkelä, Risto</creatorcontrib><creatorcontrib>Pikkarainen, Sampsa</creatorcontrib><creatorcontrib>Uusimaa, Paavo</creatorcontrib><creatorcontrib>Hautala, Timo</creatorcontrib><creatorcontrib>Vuolteenaho, Olli</creatorcontrib><creatorcontrib>Ruskoaho, Heikki</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The journal of gene medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leskinen, Hanna</au><au>Rauma-Pinola, Tanja</au><au>Szokodi, István</au><au>Kerkelä, Risto</au><au>Pikkarainen, Sampsa</au><au>Uusimaa, Paavo</au><au>Hautala, Timo</au><au>Vuolteenaho, Olli</au><au>Ruskoaho, Heikki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart</atitle><jtitle>The journal of gene medicine</jtitle><addtitle>J. Gene Med</addtitle><date>2008-08</date><risdate>2008</risdate><volume>10</volume><issue>8</issue><spage>867</spage><epage>877</epage><pages>867-877</pages><issn>1099-498X</issn><eissn>1521-2254</eissn><abstract><![CDATA[Background
Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide produced in the heart, but controversy persists regarding its cardiac effects. We explored the potential role of AM on cardiac function and remodeling by direct recombinant adenoviral AM gene delivery into the anterior wall of the left ventricle (LV).
Methods
AM was overexpressed in healthy rat hearts and in hearts during the remodeling process in response to pressure overload and myocardial infarction. The AM effects were analysed with echocardiography and in an isolated perfused rat heart preparation. The expression of AM and the activation of underlying signaling pathways were also investigated.
Results
AM mRNA increased by 20.9‐fold (p < 0.001) in healthy rat heart and improved fractional shortening by 14% (p < 0.05) and ejection fraction by 8% (p < 0.05). In isolated perfused hearts, an increase (p < 0.05) in the first derivative of isovolumic LV pressure rise (dP/dtmax) without alteration in diastolic properties was noted. The overexpression of AM activated protein kinase Cε and Cδ isoforms in the LV, whereas p38 mitogen‐activated protein kinase activity decreased. Angiotensin II‐induced LV hypertrophy was significantly attenuated by AM (p < 0.01) without compromising cardiac contractility. By contrast, AM enhanced LV dilatation (p < 0.01) and anterior wall thinning (p < 0.001) and augmented the deterioration of LV function (p < 0.05) post‐infarction.
Conclusions
The results obtained in the present study show that AM overexpression improves LV systolic function without altering cardiac diastolic properties in the normal heart. Moreover, AM is a potent context‐dependent modulator of LV remodeling because it promotes an adaptive response in pressure overload‐induced LV hypertrophy and triggers a maladaptive process in post‐infarction remodeling. Copyright © 2008 John Wiley & Sons, Ltd.]]></abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>18615773</pmid><doi>10.1002/jgm.1219</doi><tpages>11</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adenoviridae - drug effects Adrenomedullin - metabolism Adrenomedullin - pharmacology Animals Gene therapy gene transfer Gene Transfer Techniques Heart - drug effects Heart - physiology Heart - physiopathology Heart Ventricles - drug effects hypertrophy Hypertrophy, Left Ventricular - metabolism Hypertrophy, Left Ventricular - physiopathology left ventricular remodeling Male myocardial infarction Myocardial Infarction - physiopathology Myocardium - metabolism Rats Rats, Sprague-Dawley RNA, Messenger - metabolism Systole - drug effects systolic function Ventricular Function, Left - drug effects |
| title | Adaptive or maladaptive response to adenoviral adrenomedullin gene transfer is context-dependent in the heart |
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