Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease
Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to s...
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| Veröffentlicht in: | Biochimica et biophysica acta. Molecular basis of disease 2018-01, Vol.1864 (1), p.11-23 |
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| creator | Caballero, Eugenia Pérez Santamaría, Miguel H. Corral, Ricardo S. |
| description | Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 −/−) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 −/− infection showed lower heart-to-body ratio (P |
| doi_str_mv | 10.1016/j.bbadis.2017.10.006 |
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•Endogenous osteopontin (OPN) is crucial for pathogenesis of Chagas cardiomyopathy.•Myocardial OPN is strongly expressed in chronically infected mice.•OPN induces CCL5/MMP-2 expression in CD8+ T cells invading T. cruzi-infected heart.•CD8+ T cells infiltrating cardiac tissue produce CCL5/MMP-2 via JNK signaling pathway.•Myocardial OPN/CCL5/MMP-2 levels correlate with increased inflammation and fibrosis.]]></description><identifier>ISSN: 0925-4439</identifier><identifier>EISSN: 1879-260X</identifier><identifier>DOI: 10.1016/j.bbadis.2017.10.006</identifier><identifier>PMID: 28987763</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Atrial Remodeling - genetics ; Atrial Remodeling - immunology ; Cardiac remodeling ; Cells, Cultured ; Chagas cardiomyopathy ; Chagas Cardiomyopathy - genetics ; Chagas Cardiomyopathy - immunology ; Chagas Cardiomyopathy - metabolism ; Chagas Cardiomyopathy - pathology ; Chemokine CCL5 - metabolism ; Disease Models, Animal ; Endomyocardial Fibrosis - genetics ; Endomyocardial Fibrosis - metabolism ; Endomyocardial Fibrosis - pathology ; Inflammation ; Inflammation - genetics ; Inflammation - metabolism ; Inflammation - pathology ; Male ; Matrix Metalloproteinase 2 - metabolism ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Knockout ; Myocarditis - genetics ; Myocarditis - immunology ; Myocarditis - metabolism ; Myocarditis - pathology ; Myocardium - immunology ; Myocardium - metabolism ; Myocardium - pathology ; Osteopontin ; Osteopontin - genetics ; Osteopontin - physiology ; Trypanosoma cruzi ; Ventricular Remodeling - genetics ; Ventricular Remodeling - immunology</subject><ispartof>Biochimica et biophysica acta. Molecular basis of disease, 2018-01, Vol.1864 (1), p.11-23</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-b644618f31a68cf76914152b21e660cbc7a0f41626a25dffdbd30a712d8f2d013</citedby><cites>FETCH-LOGICAL-c408t-b644618f31a68cf76914152b21e660cbc7a0f41626a25dffdbd30a712d8f2d013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bbadis.2017.10.006$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28987763$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Caballero, Eugenia Pérez</creatorcontrib><creatorcontrib>Santamaría, Miguel H.</creatorcontrib><creatorcontrib>Corral, Ricardo S.</creatorcontrib><title>Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease</title><title>Biochimica et biophysica acta. Molecular basis of disease</title><addtitle>Biochim Biophys Acta Mol Basis Dis</addtitle><description><![CDATA[Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 −/−) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 −/− infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 −/− mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 −/− littermates. CCL5 and MMP-2 induction occurred preferentially (P<0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P<0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.
•Endogenous osteopontin (OPN) is crucial for pathogenesis of Chagas cardiomyopathy.•Myocardial OPN is strongly expressed in chronically infected mice.•OPN induces CCL5/MMP-2 expression in CD8+ T cells invading T. cruzi-infected heart.•CD8+ T cells infiltrating cardiac tissue produce CCL5/MMP-2 via JNK signaling pathway.•Myocardial OPN/CCL5/MMP-2 levels correlate with increased inflammation and fibrosis.]]></description><subject>Animals</subject><subject>Atrial Remodeling - genetics</subject><subject>Atrial Remodeling - immunology</subject><subject>Cardiac remodeling</subject><subject>Cells, Cultured</subject><subject>Chagas cardiomyopathy</subject><subject>Chagas Cardiomyopathy - genetics</subject><subject>Chagas Cardiomyopathy - immunology</subject><subject>Chagas Cardiomyopathy - metabolism</subject><subject>Chagas Cardiomyopathy - pathology</subject><subject>Chemokine CCL5 - metabolism</subject><subject>Disease Models, Animal</subject><subject>Endomyocardial Fibrosis - genetics</subject><subject>Endomyocardial Fibrosis - metabolism</subject><subject>Endomyocardial Fibrosis - pathology</subject><subject>Inflammation</subject><subject>Inflammation - genetics</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Male</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocarditis - genetics</subject><subject>Myocarditis - immunology</subject><subject>Myocarditis - metabolism</subject><subject>Myocarditis - pathology</subject><subject>Myocardium - immunology</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - pathology</subject><subject>Osteopontin</subject><subject>Osteopontin - genetics</subject><subject>Osteopontin - physiology</subject><subject>Trypanosoma cruzi</subject><subject>Ventricular Remodeling - genetics</subject><subject>Ventricular Remodeling - immunology</subject><issn>0925-4439</issn><issn>1879-260X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2KFDEUhQtRnHb0DUSydFNtkkqnqjaCFOMP9KALBXfhVnLTnaYqaZPUwLzTPKRpa3RpNoHLd865l1NVrxndMsrku9N2HMG4tOWUtWW0pVQ-qTasa_uaS_rzabWhPd_VQjT9VfUipRMtT7b0eXXFu75rW9lsqocbb8IBfVgSCSljOAefnSfOm0VjIvN90BCNg4kMw35HwBtye_ut5gR0dneQXfAkHyETXYTRjUsuqhyKgZ1gnlfgolptNIk4B4OT84fCECBziUbyZ0aCJfoYg3eaDEc4QCJHhJhJORMh4cvqmYUp4avH_7r68fHm-_C53n_99GX4sK-1oF2uRymEZJ1tGMhO21b2TLAdHzlDKakedQvUCia5BL4z1prRNBRaxk1nuaGsua7err7nGH4tmLKaXdI4TeCxbKtYL3raSc5FQcWK6hhSimjVOboZ4r1iVF16Uie19qQuPV2mpYQie_OYsIwzmn-iv8UU4P0KYLnzzmFUSTv0Go2LqLMywf0_4TcgWaiK</recordid><startdate>201801</startdate><enddate>201801</enddate><creator>Caballero, Eugenia Pérez</creator><creator>Santamaría, Miguel H.</creator><creator>Corral, Ricardo S.</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope></search><sort><creationdate>201801</creationdate><title>Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease</title><author>Caballero, Eugenia Pérez ; Santamaría, Miguel H. ; Corral, Ricardo S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-b644618f31a68cf76914152b21e660cbc7a0f41626a25dffdbd30a712d8f2d013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Atrial Remodeling - genetics</topic><topic>Atrial Remodeling - immunology</topic><topic>Cardiac remodeling</topic><topic>Cells, Cultured</topic><topic>Chagas cardiomyopathy</topic><topic>Chagas Cardiomyopathy - genetics</topic><topic>Chagas Cardiomyopathy - immunology</topic><topic>Chagas Cardiomyopathy - metabolism</topic><topic>Chagas Cardiomyopathy - pathology</topic><topic>Chemokine CCL5 - metabolism</topic><topic>Disease Models, Animal</topic><topic>Endomyocardial Fibrosis - genetics</topic><topic>Endomyocardial Fibrosis - metabolism</topic><topic>Endomyocardial Fibrosis - pathology</topic><topic>Inflammation</topic><topic>Inflammation - genetics</topic><topic>Inflammation - metabolism</topic><topic>Inflammation - pathology</topic><topic>Male</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocarditis - genetics</topic><topic>Myocarditis - immunology</topic><topic>Myocarditis - metabolism</topic><topic>Myocarditis - pathology</topic><topic>Myocardium - immunology</topic><topic>Myocardium - metabolism</topic><topic>Myocardium - pathology</topic><topic>Osteopontin</topic><topic>Osteopontin - genetics</topic><topic>Osteopontin - physiology</topic><topic>Trypanosoma cruzi</topic><topic>Ventricular Remodeling - genetics</topic><topic>Ventricular Remodeling - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Caballero, Eugenia Pérez</creatorcontrib><creatorcontrib>Santamaría, Miguel H.</creatorcontrib><creatorcontrib>Corral, Ricardo S.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochimica et biophysica acta. Molecular basis of disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Caballero, Eugenia Pérez</au><au>Santamaría, Miguel H.</au><au>Corral, Ricardo S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease</atitle><jtitle>Biochimica et biophysica acta. Molecular basis of disease</jtitle><addtitle>Biochim Biophys Acta Mol Basis Dis</addtitle><date>2018-01</date><risdate>2018</risdate><volume>1864</volume><issue>1</issue><spage>11</spage><epage>23</epage><pages>11-23</pages><issn>0925-4439</issn><eissn>1879-260X</eissn><abstract><![CDATA[Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 −/−) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 −/− infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 −/− mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 −/− littermates. CCL5 and MMP-2 induction occurred preferentially (P<0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P<0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.
•Endogenous osteopontin (OPN) is crucial for pathogenesis of Chagas cardiomyopathy.•Myocardial OPN is strongly expressed in chronically infected mice.•OPN induces CCL5/MMP-2 expression in CD8+ T cells invading T. cruzi-infected heart.•CD8+ T cells infiltrating cardiac tissue produce CCL5/MMP-2 via JNK signaling pathway.•Myocardial OPN/CCL5/MMP-2 levels correlate with increased inflammation and fibrosis.]]></abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>28987763</pmid><doi>10.1016/j.bbadis.2017.10.006</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Atrial Remodeling - genetics Atrial Remodeling - immunology Cardiac remodeling Cells, Cultured Chagas cardiomyopathy Chagas Cardiomyopathy - genetics Chagas Cardiomyopathy - immunology Chagas Cardiomyopathy - metabolism Chagas Cardiomyopathy - pathology Chemokine CCL5 - metabolism Disease Models, Animal Endomyocardial Fibrosis - genetics Endomyocardial Fibrosis - metabolism Endomyocardial Fibrosis - pathology Inflammation Inflammation - genetics Inflammation - metabolism Inflammation - pathology Male Matrix Metalloproteinase 2 - metabolism Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Myocarditis - genetics Myocarditis - immunology Myocarditis - metabolism Myocarditis - pathology Myocardium - immunology Myocardium - metabolism Myocardium - pathology Osteopontin Osteopontin - genetics Osteopontin - physiology Trypanosoma cruzi Ventricular Remodeling - genetics Ventricular Remodeling - immunology |
| title | Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease |
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