Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction
Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptor...
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| Veröffentlicht in: | Circulation research 2008-02, Vol.102 (2), p.257-264 |
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| creator | Timmers, Leo Sluijter, Joost P.G van Keulen, J Karlijn Hoefer, Imo E Nederhoff, Marcel G.J Goumans, Marie-Jose Doevendans, Pieter A van Echteld, Cees J.A Joles, Jaap A Quax, Paul H Piek, Jan J Pasterkamp, Gerard de Kleijn, Dominique P.V |
| description | Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4 mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume103.7±6.8 μL versus 128.5±5.7 μL; P |
| doi_str_mv | 10.1161/CIRCRESAHA.107.158220 |
| format | Article |
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Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4 mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume103.7±6.8 μL versus 128.5±5.7 μL; P<0.01) and preserved systolic function (ejection fraction28.2±3.1% versus 16.6±1.3%; P<0.01), as assessed by MRI. In the noninfarcted area, interstitial fibrosis, and myocardial hypertrophy were reduced in C3H-Tlr4 mice. In the infarcted area, however, collagen density was increased, which was accompanied by fewer macrophages, reduced inflammation regulating cytokine expression levels (interleukin [IL]-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, granulocyte/macrophage colony-stimulating factor), and reduced matrix metalloproteinase-2 (4684±515 versus 7573±611; P=0.002) and matrix metalloproteinase-9 activity (76.0±14.3 versus 168.0±36.2; P=0.027). These data provide direct evidence for a causal role of TLR4 in postinfarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the treatment of ischemic heart failure.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/CIRCRESAHA.107.158220</identifier><identifier>PMID: 18007026</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Animals ; Biological and medical sciences ; Cardiology. Vascular system ; Coronary heart disease ; Cytokines - genetics ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation ; Heart ; Heart - physiopathology ; Heart Failure - therapy ; Heart failure, cardiogenic pulmonary edema, cardiac enlargement ; Medical sciences ; Mice ; Myocardial Infarction - physiopathology ; Stroke Volume ; Toll-Like Receptor 4 - deficiency ; Toll-Like Receptor 4 - physiology ; Ventricular Remodeling ; Vertebrates: cardiovascular system</subject><ispartof>Circulation research, 2008-02, Vol.102 (2), p.257-264</ispartof><rights>2008 American Heart Association, Inc.</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6200-b0bf1695c66e7b89fee7355ed65af2f6dcaeccf2f35faa70ec77f0c46512ff0f3</citedby><cites>FETCH-LOGICAL-c6200-b0bf1695c66e7b89fee7355ed65af2f6dcaeccf2f35faa70ec77f0c46512ff0f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20056544$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18007026$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Timmers, Leo</creatorcontrib><creatorcontrib>Sluijter, Joost P.G</creatorcontrib><creatorcontrib>van Keulen, J Karlijn</creatorcontrib><creatorcontrib>Hoefer, Imo E</creatorcontrib><creatorcontrib>Nederhoff, Marcel G.J</creatorcontrib><creatorcontrib>Goumans, Marie-Jose</creatorcontrib><creatorcontrib>Doevendans, Pieter A</creatorcontrib><creatorcontrib>van Echteld, Cees J.A</creatorcontrib><creatorcontrib>Joles, Jaap A</creatorcontrib><creatorcontrib>Quax, Paul H</creatorcontrib><creatorcontrib>Piek, Jan J</creatorcontrib><creatorcontrib>Pasterkamp, Gerard</creatorcontrib><creatorcontrib>de Kleijn, Dominique P.V</creatorcontrib><title>Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4 mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume103.7±6.8 μL versus 128.5±5.7 μL; P<0.01) and preserved systolic function (ejection fraction28.2±3.1% versus 16.6±1.3%; P<0.01), as assessed by MRI. In the noninfarcted area, interstitial fibrosis, and myocardial hypertrophy were reduced in C3H-Tlr4 mice. In the infarcted area, however, collagen density was increased, which was accompanied by fewer macrophages, reduced inflammation regulating cytokine expression levels (interleukin [IL]-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, granulocyte/macrophage colony-stimulating factor), and reduced matrix metalloproteinase-2 (4684±515 versus 7573±611; P=0.002) and matrix metalloproteinase-9 activity (76.0±14.3 versus 168.0±36.2; P=0.027). These data provide direct evidence for a causal role of TLR4 in postinfarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the treatment of ischemic heart failure.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Coronary heart disease</subject><subject>Cytokines - genetics</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression Regulation</subject><subject>Heart</subject><subject>Heart - physiopathology</subject><subject>Heart Failure - therapy</subject><subject>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Myocardial Infarction - physiopathology</subject><subject>Stroke Volume</subject><subject>Toll-Like Receptor 4 - deficiency</subject><subject>Toll-Like Receptor 4 - physiology</subject><subject>Ventricular Remodeling</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxS0EokvhI4B8gVuWsRM7m-MqaulKu0JaCtdo1hlTU-cPdtKqFz47pruix57Gmvd7tvUeY-8FLIXQ4nO92df7i2_rq_VSQLkUaiUlvGALoWSRFaoUL9kCAKqszHM4Y29i_AUgilxWr9mZWAGUIPWC_bkevM-27pb4ngyN0xB4wXfUOpwo8h16bHGc3B3xLdmJ_6B-Cs7MHkMydENL3vU_OfYt33QjuhB5jSG5Db-cezO5oedrO1Hgu4fBPCqeb3qL4VF7y15Z9JHeneY5-355cV1fZduvXzb1epsZLQGyAxys0JUyWlN5WFWWqMyVolYrtNLq1iAZk065soglkClLC6bQSkhrwebn7NPx3jEMv2eKU9O5aMh77GmYY5PCSJmt9LOgBFVJWVQJVEfQhCHGQLYZg-swPDQCmn8NNU8NpVXZHBtKvg-nB-ZDR-2T61RJAj6eAIwGvQ3YGxf_cykOpVVRJK46cveDT_nGWz_fU2huCP1088wn_gLq2a4t</recordid><startdate>20080201</startdate><enddate>20080201</enddate><creator>Timmers, Leo</creator><creator>Sluijter, Joost P.G</creator><creator>van Keulen, J Karlijn</creator><creator>Hoefer, Imo E</creator><creator>Nederhoff, Marcel G.J</creator><creator>Goumans, Marie-Jose</creator><creator>Doevendans, Pieter A</creator><creator>van Echteld, Cees J.A</creator><creator>Joles, Jaap A</creator><creator>Quax, Paul H</creator><creator>Piek, Jan J</creator><creator>Pasterkamp, Gerard</creator><creator>de Kleijn, Dominique P.V</creator><general>American Heart Association, Inc</general><general>Lippincott</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20080201</creationdate><title>Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction</title><author>Timmers, Leo ; Sluijter, Joost P.G ; van Keulen, J Karlijn ; Hoefer, Imo E ; Nederhoff, Marcel G.J ; Goumans, Marie-Jose ; Doevendans, Pieter A ; van Echteld, Cees J.A ; Joles, Jaap A ; Quax, Paul H ; Piek, Jan J ; Pasterkamp, Gerard ; de Kleijn, Dominique P.V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6200-b0bf1695c66e7b89fee7355ed65af2f6dcaeccf2f35faa70ec77f0c46512ff0f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cardiology. 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Psychology</topic><topic>Gene Expression Regulation</topic><topic>Heart</topic><topic>Heart - physiopathology</topic><topic>Heart Failure - therapy</topic><topic>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Myocardial Infarction - physiopathology</topic><topic>Stroke Volume</topic><topic>Toll-Like Receptor 4 - deficiency</topic><topic>Toll-Like Receptor 4 - physiology</topic><topic>Ventricular Remodeling</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Timmers, Leo</creatorcontrib><creatorcontrib>Sluijter, Joost P.G</creatorcontrib><creatorcontrib>van Keulen, J Karlijn</creatorcontrib><creatorcontrib>Hoefer, Imo E</creatorcontrib><creatorcontrib>Nederhoff, Marcel G.J</creatorcontrib><creatorcontrib>Goumans, Marie-Jose</creatorcontrib><creatorcontrib>Doevendans, Pieter A</creatorcontrib><creatorcontrib>van Echteld, Cees J.A</creatorcontrib><creatorcontrib>Joles, Jaap A</creatorcontrib><creatorcontrib>Quax, Paul H</creatorcontrib><creatorcontrib>Piek, Jan J</creatorcontrib><creatorcontrib>Pasterkamp, Gerard</creatorcontrib><creatorcontrib>de Kleijn, Dominique P.V</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Timmers, Leo</au><au>Sluijter, Joost P.G</au><au>van Keulen, J Karlijn</au><au>Hoefer, Imo E</au><au>Nederhoff, Marcel G.J</au><au>Goumans, Marie-Jose</au><au>Doevendans, Pieter A</au><au>van Echteld, Cees J.A</au><au>Joles, Jaap A</au><au>Quax, Paul H</au><au>Piek, Jan J</au><au>Pasterkamp, Gerard</au><au>de Kleijn, Dominique P.V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2008-02-01</date><risdate>2008</risdate><volume>102</volume><issue>2</issue><spage>257</spage><epage>264</epage><pages>257-264</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4 mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume103.7±6.8 μL versus 128.5±5.7 μL; P<0.01) and preserved systolic function (ejection fraction28.2±3.1% versus 16.6±1.3%; P<0.01), as assessed by MRI. In the noninfarcted area, interstitial fibrosis, and myocardial hypertrophy were reduced in C3H-Tlr4 mice. In the infarcted area, however, collagen density was increased, which was accompanied by fewer macrophages, reduced inflammation regulating cytokine expression levels (interleukin [IL]-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, granulocyte/macrophage colony-stimulating factor), and reduced matrix metalloproteinase-2 (4684±515 versus 7573±611; P=0.002) and matrix metalloproteinase-9 activity (76.0±14.3 versus 168.0±36.2; P=0.027). These data provide direct evidence for a causal role of TLR4 in postinfarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the treatment of ischemic heart failure.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>18007026</pmid><doi>10.1161/CIRCRESAHA.107.158220</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Cardiology. Vascular system Coronary heart disease Cytokines - genetics Fundamental and applied biological sciences. Psychology Gene Expression Regulation Heart Heart - physiopathology Heart Failure - therapy Heart failure, cardiogenic pulmonary edema, cardiac enlargement Medical sciences Mice Myocardial Infarction - physiopathology Stroke Volume Toll-Like Receptor 4 - deficiency Toll-Like Receptor 4 - physiology Ventricular Remodeling Vertebrates: cardiovascular system |
| title | Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction |
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