Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model
Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a g...
Gespeichert in:
| Veröffentlicht in: | Physiological reports 2017-03, Vol.5 (5), p.np-n/a |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | n/a |
|---|---|
| container_issue | 5 |
| container_start_page | np |
| container_title | Physiological reports |
| container_volume | 5 |
| creator | Munjal, Charu Jegga, Anil G. Opoka, Amy M. Stoilov, Ivan Norris, Russell A. Thomas, Craig J. Smith, J. Michael Mecham, Robert P. Bressan, Giorgio M. Hinton, Robert B. |
| description | Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1‐deficient mouse (Emilin1−/−) is a model of latent AVD, characterized by activated TGFβ/MEK/p‐Erk signaling and upregulated elastase activity. Emilin1−/− aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12–14 months) Emilin1−/− mice were treated with refametinib (RDEA‐119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6‐31 (anti‐VEGF‐A mouse antibody) for 4 weeks. Refametinib‐ and doxycycline‐treated Emilin1−/− mice markedly reduced MEK/p‐Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP‐2, and MMP‐9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1−/− aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1−/− and age‐matched wild‐type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p‐Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression
This study demonstrates the effectiveness of MEK1/2 inhibition using refametinib, and to a lesser extent elastase inhibition using doxycycline, in the Emilin1‐deficient mouse model of latent aortic valve disease. These findings have important clinical implications because understanding early disease mechanisms promises to identify new medical therapies. |
| doi_str_mv | 10.14814/phy2.13152 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5350168</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1881763817</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5132-219920ffa9e791d8f29281e23828ac90cac34530376f17fe787644defa1be4b13</originalsourceid><addsrcrecordid>eNp9kc1qFTEYhoMottSu3EvAjSCn5ktmzmQ2QimnP1ixiwq6CjmZL57UmWRMZqacnZfgJXgtXkqvpGlPLbULN0kgD0_eLy8hL4HtQSGheNev1nwPBJT8CdnmrISZhOrL0wfnLbKb0gVjDJgQNSueky0uecXKmm2T6cSv3NINLngaLP24f_bh6uevRfxOez2sLvWaOv_n9-SmQPUwoB_1gInqEAdn6KTbCWnjEuqEtI_BYEr52nm66FzrPGRXg9YZh36gXRgz1oUG2xfkmdVtwt27fYd8PlycHxzPTj8dnRzsn85MCYLPONQ1Z9bqGqsaGml5zSUgF5JLbWpmtBFFKZio5hYqi5Ws5kWRX9SwxGIJYoe833j7cdlhY3KMqFvVR9fpuFZBO_XvjXcr9S1MqhQlg7nMgjd3ghh-jJgG1blksG21xzyOApm_eC7yktHXj9CLMEafx1Oc1wxugpaZeruhTAwpRbT3YYCp20rVTaXqttJMv3qY_579W2AG-Aa4dC2u_-dSZ8df-cZ6DZoAr8M</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2290145305</pqid></control><display><type>article</type><title>Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Wiley-Blackwell Open Access Titles</source><source>Wiley Online Library All Journals</source><source>PubMed Central</source><creator>Munjal, Charu ; Jegga, Anil G. ; Opoka, Amy M. ; Stoilov, Ivan ; Norris, Russell A. ; Thomas, Craig J. ; Smith, J. Michael ; Mecham, Robert P. ; Bressan, Giorgio M. ; Hinton, Robert B.</creator><creatorcontrib>Munjal, Charu ; Jegga, Anil G. ; Opoka, Amy M. ; Stoilov, Ivan ; Norris, Russell A. ; Thomas, Craig J. ; Smith, J. Michael ; Mecham, Robert P. ; Bressan, Giorgio M. ; Hinton, Robert B.</creatorcontrib><description>Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1‐deficient mouse (Emilin1−/−) is a model of latent AVD, characterized by activated TGFβ/MEK/p‐Erk signaling and upregulated elastase activity. Emilin1−/− aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12–14 months) Emilin1−/− mice were treated with refametinib (RDEA‐119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6‐31 (anti‐VEGF‐A mouse antibody) for 4 weeks. Refametinib‐ and doxycycline‐treated Emilin1−/− mice markedly reduced MEK/p‐Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP‐2, and MMP‐9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1−/− aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1−/− and age‐matched wild‐type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p‐Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression
This study demonstrates the effectiveness of MEK1/2 inhibition using refametinib, and to a lesser extent elastase inhibition using doxycycline, in the Emilin1‐deficient mouse model of latent aortic valve disease. These findings have important clinical implications because understanding early disease mechanisms promises to identify new medical therapies.</description><identifier>ISSN: 2051-817X</identifier><identifier>EISSN: 2051-817X</identifier><identifier>DOI: 10.14814/phy2.13152</identifier><identifier>PMID: 28270590</identifier><language>eng</language><publisher>United States: John Wiley & Sons, Inc</publisher><subject>Age ; Ageing and Degeneration ; Angiogenesis ; Animals ; Antibodies - pharmacology ; Antibodies - therapeutic use ; Aortic valve ; Aortic Valve - drug effects ; Aortic Valve - metabolism ; Aortic Valve - pathology ; Bicuspid Aortic Valve Disease ; Cardiovascular Conditions, Disorders and Treatments ; Cathepsin K ; Cell activation ; Clinical trials ; Dietary fiber ; Diphenylamine - analogs & derivatives ; Diphenylamine - pharmacology ; Diphenylamine - therapeutic use ; Disease Models, Animal ; Disease Progression ; Doxycycline ; Doxycycline - pharmacology ; Doxycycline - therapeutic use ; Drug dosages ; Elastase ; elastases ; elastic fibers ; Elastin microfibril interface located protein ; Enzymes ; Extracellular signal-regulated kinase ; Fibrosis ; Heart Defects, Congenital - drug therapy ; Heart Defects, Congenital - metabolism ; Heart Defects, Congenital - pathology ; Heart Valve Diseases - drug therapy ; Heart Valve Diseases - metabolism ; Heart Valve Diseases - pathology ; Immunology ; Inflammation ; Macrophages ; MAP kinase ; MAP Kinase Signaling System - drug effects ; Membrane Glycoproteins - genetics ; Metabolic pathways ; Mice ; Mice, Knockout ; Original Research ; Pancreatic Elastase - metabolism ; Regulatory Pathways ; Signal transduction ; Signalling Pathways ; Software ; Studies ; Sulfonamides - pharmacology ; Sulfonamides - therapeutic use ; Up-Regulation - drug effects ; valves ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - immunology ; Vascularization</subject><ispartof>Physiological reports, 2017-03, Vol.5 (5), p.np-n/a</ispartof><rights>2017 Cincinnati Children's Hospital. published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.</rights><rights>2017 Cincinnati Children's Hospital. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.</rights><rights>2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5132-219920ffa9e791d8f29281e23828ac90cac34530376f17fe787644defa1be4b13</citedby><cites>FETCH-LOGICAL-c5132-219920ffa9e791d8f29281e23828ac90cac34530376f17fe787644defa1be4b13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350168/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350168/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28270590$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Munjal, Charu</creatorcontrib><creatorcontrib>Jegga, Anil G.</creatorcontrib><creatorcontrib>Opoka, Amy M.</creatorcontrib><creatorcontrib>Stoilov, Ivan</creatorcontrib><creatorcontrib>Norris, Russell A.</creatorcontrib><creatorcontrib>Thomas, Craig J.</creatorcontrib><creatorcontrib>Smith, J. Michael</creatorcontrib><creatorcontrib>Mecham, Robert P.</creatorcontrib><creatorcontrib>Bressan, Giorgio M.</creatorcontrib><creatorcontrib>Hinton, Robert B.</creatorcontrib><title>Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model</title><title>Physiological reports</title><addtitle>Physiol Rep</addtitle><description>Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1‐deficient mouse (Emilin1−/−) is a model of latent AVD, characterized by activated TGFβ/MEK/p‐Erk signaling and upregulated elastase activity. Emilin1−/− aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12–14 months) Emilin1−/− mice were treated with refametinib (RDEA‐119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6‐31 (anti‐VEGF‐A mouse antibody) for 4 weeks. Refametinib‐ and doxycycline‐treated Emilin1−/− mice markedly reduced MEK/p‐Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP‐2, and MMP‐9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1−/− aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1−/− and age‐matched wild‐type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p‐Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression
This study demonstrates the effectiveness of MEK1/2 inhibition using refametinib, and to a lesser extent elastase inhibition using doxycycline, in the Emilin1‐deficient mouse model of latent aortic valve disease. These findings have important clinical implications because understanding early disease mechanisms promises to identify new medical therapies.</description><subject>Age</subject><subject>Ageing and Degeneration</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Antibodies - pharmacology</subject><subject>Antibodies - therapeutic use</subject><subject>Aortic valve</subject><subject>Aortic Valve - drug effects</subject><subject>Aortic Valve - metabolism</subject><subject>Aortic Valve - pathology</subject><subject>Bicuspid Aortic Valve Disease</subject><subject>Cardiovascular Conditions, Disorders and Treatments</subject><subject>Cathepsin K</subject><subject>Cell activation</subject><subject>Clinical trials</subject><subject>Dietary fiber</subject><subject>Diphenylamine - analogs & derivatives</subject><subject>Diphenylamine - pharmacology</subject><subject>Diphenylamine - therapeutic use</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Doxycycline</subject><subject>Doxycycline - pharmacology</subject><subject>Doxycycline - therapeutic use</subject><subject>Drug dosages</subject><subject>Elastase</subject><subject>elastases</subject><subject>elastic fibers</subject><subject>Elastin microfibril interface located protein</subject><subject>Enzymes</subject><subject>Extracellular signal-regulated kinase</subject><subject>Fibrosis</subject><subject>Heart Defects, Congenital - drug therapy</subject><subject>Heart Defects, Congenital - metabolism</subject><subject>Heart Defects, Congenital - pathology</subject><subject>Heart Valve Diseases - drug therapy</subject><subject>Heart Valve Diseases - metabolism</subject><subject>Heart Valve Diseases - pathology</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Macrophages</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Metabolic pathways</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Original Research</subject><subject>Pancreatic Elastase - metabolism</subject><subject>Regulatory Pathways</subject><subject>Signal transduction</subject><subject>Signalling Pathways</subject><subject>Software</subject><subject>Studies</subject><subject>Sulfonamides - pharmacology</subject><subject>Sulfonamides - therapeutic use</subject><subject>Up-Regulation - drug effects</subject><subject>valves</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - immunology</subject><subject>Vascularization</subject><issn>2051-817X</issn><issn>2051-817X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc1qFTEYhoMottSu3EvAjSCn5ktmzmQ2QimnP1ixiwq6CjmZL57UmWRMZqacnZfgJXgtXkqvpGlPLbULN0kgD0_eLy8hL4HtQSGheNev1nwPBJT8CdnmrISZhOrL0wfnLbKb0gVjDJgQNSueky0uecXKmm2T6cSv3NINLngaLP24f_bh6uevRfxOez2sLvWaOv_n9-SmQPUwoB_1gInqEAdn6KTbCWnjEuqEtI_BYEr52nm66FzrPGRXg9YZh36gXRgz1oUG2xfkmdVtwt27fYd8PlycHxzPTj8dnRzsn85MCYLPONQ1Z9bqGqsaGml5zSUgF5JLbWpmtBFFKZio5hYqi5Ws5kWRX9SwxGIJYoe833j7cdlhY3KMqFvVR9fpuFZBO_XvjXcr9S1MqhQlg7nMgjd3ghh-jJgG1blksG21xzyOApm_eC7yktHXj9CLMEafx1Oc1wxugpaZeruhTAwpRbT3YYCp20rVTaXqttJMv3qY_579W2AG-Aa4dC2u_-dSZ8df-cZ6DZoAr8M</recordid><startdate>201703</startdate><enddate>201703</enddate><creator>Munjal, Charu</creator><creator>Jegga, Anil G.</creator><creator>Opoka, Amy M.</creator><creator>Stoilov, Ivan</creator><creator>Norris, Russell A.</creator><creator>Thomas, Craig J.</creator><creator>Smith, J. Michael</creator><creator>Mecham, Robert P.</creator><creator>Bressan, Giorgio M.</creator><creator>Hinton, Robert B.</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</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>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</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>CCPQU</scope><scope>DWQXO</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>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>201703</creationdate><title>Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model</title><author>Munjal, Charu ; Jegga, Anil G. ; Opoka, Amy M. ; Stoilov, Ivan ; Norris, Russell A. ; Thomas, Craig J. ; Smith, J. Michael ; Mecham, Robert P. ; Bressan, Giorgio M. ; Hinton, Robert B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5132-219920ffa9e791d8f29281e23828ac90cac34530376f17fe787644defa1be4b13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Age</topic><topic>Ageing and Degeneration</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Antibodies - pharmacology</topic><topic>Antibodies - therapeutic use</topic><topic>Aortic valve</topic><topic>Aortic Valve - drug effects</topic><topic>Aortic Valve - metabolism</topic><topic>Aortic Valve - pathology</topic><topic>Bicuspid Aortic Valve Disease</topic><topic>Cardiovascular Conditions, Disorders and Treatments</topic><topic>Cathepsin K</topic><topic>Cell activation</topic><topic>Clinical trials</topic><topic>Dietary fiber</topic><topic>Diphenylamine - analogs & derivatives</topic><topic>Diphenylamine - pharmacology</topic><topic>Diphenylamine - therapeutic use</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Doxycycline</topic><topic>Doxycycline - pharmacology</topic><topic>Doxycycline - therapeutic use</topic><topic>Drug dosages</topic><topic>Elastase</topic><topic>elastases</topic><topic>elastic fibers</topic><topic>Elastin microfibril interface located protein</topic><topic>Enzymes</topic><topic>Extracellular signal-regulated kinase</topic><topic>Fibrosis</topic><topic>Heart Defects, Congenital - drug therapy</topic><topic>Heart Defects, Congenital - metabolism</topic><topic>Heart Defects, Congenital - pathology</topic><topic>Heart Valve Diseases - drug therapy</topic><topic>Heart Valve Diseases - metabolism</topic><topic>Heart Valve Diseases - pathology</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Macrophages</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Metabolic pathways</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Original Research</topic><topic>Pancreatic Elastase - metabolism</topic><topic>Regulatory Pathways</topic><topic>Signal transduction</topic><topic>Signalling Pathways</topic><topic>Software</topic><topic>Studies</topic><topic>Sulfonamides - pharmacology</topic><topic>Sulfonamides - therapeutic use</topic><topic>Up-Regulation - drug effects</topic><topic>valves</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - immunology</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Munjal, Charu</creatorcontrib><creatorcontrib>Jegga, Anil G.</creatorcontrib><creatorcontrib>Opoka, Amy M.</creatorcontrib><creatorcontrib>Stoilov, Ivan</creatorcontrib><creatorcontrib>Norris, Russell A.</creatorcontrib><creatorcontrib>Thomas, Craig J.</creatorcontrib><creatorcontrib>Smith, J. Michael</creatorcontrib><creatorcontrib>Mecham, Robert P.</creatorcontrib><creatorcontrib>Bressan, Giorgio M.</creatorcontrib><creatorcontrib>Hinton, Robert B.</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Physiological reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Munjal, Charu</au><au>Jegga, Anil G.</au><au>Opoka, Amy M.</au><au>Stoilov, Ivan</au><au>Norris, Russell A.</au><au>Thomas, Craig J.</au><au>Smith, J. Michael</au><au>Mecham, Robert P.</au><au>Bressan, Giorgio M.</au><au>Hinton, Robert B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model</atitle><jtitle>Physiological reports</jtitle><addtitle>Physiol Rep</addtitle><date>2017-03</date><risdate>2017</risdate><volume>5</volume><issue>5</issue><spage>np</spage><epage>n/a</epage><pages>np-n/a</pages><issn>2051-817X</issn><eissn>2051-817X</eissn><abstract>Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1‐deficient mouse (Emilin1−/−) is a model of latent AVD, characterized by activated TGFβ/MEK/p‐Erk signaling and upregulated elastase activity. Emilin1−/− aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12–14 months) Emilin1−/− mice were treated with refametinib (RDEA‐119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6‐31 (anti‐VEGF‐A mouse antibody) for 4 weeks. Refametinib‐ and doxycycline‐treated Emilin1−/− mice markedly reduced MEK/p‐Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP‐2, and MMP‐9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1−/− aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1−/− and age‐matched wild‐type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p‐Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression
This study demonstrates the effectiveness of MEK1/2 inhibition using refametinib, and to a lesser extent elastase inhibition using doxycycline, in the Emilin1‐deficient mouse model of latent aortic valve disease. These findings have important clinical implications because understanding early disease mechanisms promises to identify new medical therapies.</abstract><cop>United States</cop><pub>John Wiley & Sons, Inc</pub><pmid>28270590</pmid><doi>10.14814/phy2.13152</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2051-817X |
| ispartof | Physiological reports, 2017-03, Vol.5 (5), p.np-n/a |
| issn | 2051-817X 2051-817X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5350168 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley-Blackwell Open Access Titles; Wiley Online Library All Journals; PubMed Central |
| subjects | Age Ageing and Degeneration Angiogenesis Animals Antibodies - pharmacology Antibodies - therapeutic use Aortic valve Aortic Valve - drug effects Aortic Valve - metabolism Aortic Valve - pathology Bicuspid Aortic Valve Disease Cardiovascular Conditions, Disorders and Treatments Cathepsin K Cell activation Clinical trials Dietary fiber Diphenylamine - analogs & derivatives Diphenylamine - pharmacology Diphenylamine - therapeutic use Disease Models, Animal Disease Progression Doxycycline Doxycycline - pharmacology Doxycycline - therapeutic use Drug dosages Elastase elastases elastic fibers Elastin microfibril interface located protein Enzymes Extracellular signal-regulated kinase Fibrosis Heart Defects, Congenital - drug therapy Heart Defects, Congenital - metabolism Heart Defects, Congenital - pathology Heart Valve Diseases - drug therapy Heart Valve Diseases - metabolism Heart Valve Diseases - pathology Immunology Inflammation Macrophages MAP kinase MAP Kinase Signaling System - drug effects Membrane Glycoproteins - genetics Metabolic pathways Mice Mice, Knockout Original Research Pancreatic Elastase - metabolism Regulatory Pathways Signal transduction Signalling Pathways Software Studies Sulfonamides - pharmacology Sulfonamides - therapeutic use Up-Regulation - drug effects valves Vascular endothelial growth factor Vascular Endothelial Growth Factor A - immunology Vascularization |
| title | Inhibition of MAPK‐Erk pathway in vivo attenuates aortic valve disease processes in Emilin1‐deficient mouse model |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T11%3A45%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20MAPK%E2%80%90Erk%20pathway%20in%C2%A0vivo%20attenuates%20aortic%20valve%20disease%20processes%20in%20Emilin1%E2%80%90deficient%20mouse%20model&rft.jtitle=Physiological%20reports&rft.au=Munjal,%20Charu&rft.date=2017-03&rft.volume=5&rft.issue=5&rft.spage=np&rft.epage=n/a&rft.pages=np-n/a&rft.issn=2051-817X&rft.eissn=2051-817X&rft_id=info:doi/10.14814/phy2.13152&rft_dat=%3Cproquest_pubme%3E1881763817%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2290145305&rft_id=info:pmid/28270590&rfr_iscdi=true |