Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis
RATIONALE:Previously, we have found that changes in the location of intracellular heat shock protein (HSP)60 are associated with apoptosis. HSP60 has been reported to be a ligand of Toll-like receptor (TLR)-4. OBJECTIVE:We hypothesized that extracellular HSP60 (exHSP60) would mediate apoptosis via T...
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| Veröffentlicht in: | Circulation research 2009-12, Vol.105 (12), p.1186-1195 |
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| container_title | Circulation research |
| container_volume | 105 |
| creator | Kim, Se-Chan Stice, James P Chen, Le Jung, James S Gupta, Sanjiv Wang, Yin Baumgarten, Georg Trial, Joann Knowlton, Anne A |
| description | RATIONALE:Previously, we have found that changes in the location of intracellular heat shock protein (HSP)60 are associated with apoptosis. HSP60 has been reported to be a ligand of Toll-like receptor (TLR)-4.
OBJECTIVE:We hypothesized that extracellular HSP60 (exHSP60) would mediate apoptosis via TLR4.
METHODS AND RESULTS:Adult rat cardiac myocytes were treated with HSP60, either recombinant human or with HSP60 purified from the media of injured rat cardiac myocytes. ExHSP60 induced apoptosis in cardiac myocytes, as detected by increased caspase 3 activity and increased DNA fragmentation. Apoptosis could be reduced by blocking antibodies to TLR4 and by nuclear factor κB binding decoys, but not completely inhibited, even though similar treatment blocked lipopolysaccharide-induced apoptosis. Three distinct controls showed no evidence for involvement of a ligand other than exHSP60 in the mediation of apoptosis.
CONCLUSIONS:This is the first report of HSP60-induced apoptosis via the TLRs. HSP60-mediated activation of TLR4 may be a mechanism of myocyte loss in heart failure, where HSP60 has been detected in the plasma. |
| doi_str_mv | 10.1161/CIRCRESAHA.109.209643 |
| format | Article |
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OBJECTIVE:We hypothesized that extracellular HSP60 (exHSP60) would mediate apoptosis via TLR4.
METHODS AND RESULTS:Adult rat cardiac myocytes were treated with HSP60, either recombinant human or with HSP60 purified from the media of injured rat cardiac myocytes. ExHSP60 induced apoptosis in cardiac myocytes, as detected by increased caspase 3 activity and increased DNA fragmentation. Apoptosis could be reduced by blocking antibodies to TLR4 and by nuclear factor κB binding decoys, but not completely inhibited, even though similar treatment blocked lipopolysaccharide-induced apoptosis. Three distinct controls showed no evidence for involvement of a ligand other than exHSP60 in the mediation of apoptosis.
CONCLUSIONS:This is the first report of HSP60-induced apoptosis via the TLRs. HSP60-mediated activation of TLR4 may be a mechanism of myocyte loss in heart failure, where HSP60 has been detected in the plasma.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/CIRCRESAHA.109.209643</identifier><identifier>PMID: 19875724</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Animals ; Antibodies ; Apoptosis ; Caspase 3 - metabolism ; Chaperonin 60 - metabolism ; DNA Fragmentation ; Endotoxins - metabolism ; HSP27 Heat-Shock Proteins - metabolism ; Humans ; Interleukin-1beta - genetics ; Interleukin-6 - genetics ; Ligands ; Lipopolysaccharide Receptors - metabolism ; Male ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; NF-kappa B - metabolism ; p38 Mitogen-Activated Protein Kinases - metabolism ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins - metabolism ; RNA, Messenger - metabolism ; Signal Transduction ; Toll-Like Receptor 2 - metabolism ; Toll-Like Receptor 4 - immunology ; Toll-Like Receptor 4 - metabolism ; Tumor Necrosis Factor-alpha - genetics</subject><ispartof>Circulation research, 2009-12, Vol.105 (12), p.1186-1195</ispartof><rights>2009 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5653-b58cdc969827ba70fb26eeec6ca8a49ed2325c932928e8092029a9b5e7b9ecdf3</citedby><cites>FETCH-LOGICAL-c5653-b58cdc969827ba70fb26eeec6ca8a49ed2325c932928e8092029a9b5e7b9ecdf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3674,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19875724$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Se-Chan</creatorcontrib><creatorcontrib>Stice, James P</creatorcontrib><creatorcontrib>Chen, Le</creatorcontrib><creatorcontrib>Jung, James S</creatorcontrib><creatorcontrib>Gupta, Sanjiv</creatorcontrib><creatorcontrib>Wang, Yin</creatorcontrib><creatorcontrib>Baumgarten, Georg</creatorcontrib><creatorcontrib>Trial, Joann</creatorcontrib><creatorcontrib>Knowlton, Anne A</creatorcontrib><title>Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>RATIONALE:Previously, we have found that changes in the location of intracellular heat shock protein (HSP)60 are associated with apoptosis. HSP60 has been reported to be a ligand of Toll-like receptor (TLR)-4.
OBJECTIVE:We hypothesized that extracellular HSP60 (exHSP60) would mediate apoptosis via TLR4.
METHODS AND RESULTS:Adult rat cardiac myocytes were treated with HSP60, either recombinant human or with HSP60 purified from the media of injured rat cardiac myocytes. ExHSP60 induced apoptosis in cardiac myocytes, as detected by increased caspase 3 activity and increased DNA fragmentation. Apoptosis could be reduced by blocking antibodies to TLR4 and by nuclear factor κB binding decoys, but not completely inhibited, even though similar treatment blocked lipopolysaccharide-induced apoptosis. Three distinct controls showed no evidence for involvement of a ligand other than exHSP60 in the mediation of apoptosis.
CONCLUSIONS:This is the first report of HSP60-induced apoptosis via the TLRs. HSP60-mediated activation of TLR4 may be a mechanism of myocyte loss in heart failure, where HSP60 has been detected in the plasma.</description><subject>Animals</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Caspase 3 - metabolism</subject><subject>Chaperonin 60 - metabolism</subject><subject>DNA Fragmentation</subject><subject>Endotoxins - metabolism</subject><subject>HSP27 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Interleukin-1beta - genetics</subject><subject>Interleukin-6 - genetics</subject><subject>Ligands</subject><subject>Lipopolysaccharide Receptors - metabolism</subject><subject>Male</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>NF-kappa B - metabolism</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recombinant Proteins - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction</subject><subject>Toll-Like Receptor 2 - metabolism</subject><subject>Toll-Like Receptor 4 - immunology</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1P6zAQtBAI-oCfAMqNS9NnO7GdvSBVoY8igUB8nC3H2dJAGhc7AfrvCWr1gBOnlXZnZ2dnCDlidMSYZH_zi9v8dnI3no5HjMKIU5BpskUGTPA0ToVi22RAKYVYJQndI39CeKKUpQmHXbLHIFNC8XRAzibvrTcW67qrjY-maNrobu7sc3TjXYtVE0k6jHLjy8rY6Grl7KrFMIxMU0bjpVu2LlThgOzMTB3wcFP3ycO_yX0-jS-vzy_y8WVshRRJXIjMlhYkZFwVRtFZwSUiWmlNZlLAkidcWOgl8gwzCpxyMFAIVAWgLWfJPjld8y67YoGlxabXXuulrxbGr7Qzlf45aaq5fnSvmkMKXMme4GRD4N1Lh6HViyp8Pm8adF3QvVeSJpKrHinWSOtdCB5n_68wqj8D0F8B9C3Q6wD6vePvEr-2No73AFgD3lzdog_PdfeGXs_R1O38F_IPxMCVGQ</recordid><startdate>20091204</startdate><enddate>20091204</enddate><creator>Kim, Se-Chan</creator><creator>Stice, James P</creator><creator>Chen, Le</creator><creator>Jung, James S</creator><creator>Gupta, Sanjiv</creator><creator>Wang, Yin</creator><creator>Baumgarten, Georg</creator><creator>Trial, Joann</creator><creator>Knowlton, Anne A</creator><general>American Heart Association, Inc</general><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><scope>5PM</scope></search><sort><creationdate>20091204</creationdate><title>Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis</title><author>Kim, Se-Chan ; Stice, James P ; Chen, Le ; Jung, James S ; Gupta, Sanjiv ; Wang, Yin ; Baumgarten, Georg ; Trial, Joann ; Knowlton, Anne A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5653-b58cdc969827ba70fb26eeec6ca8a49ed2325c932928e8092029a9b5e7b9ecdf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>Caspase 3 - metabolism</topic><topic>Chaperonin 60 - metabolism</topic><topic>DNA Fragmentation</topic><topic>Endotoxins - metabolism</topic><topic>HSP27 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Interleukin-1beta - genetics</topic><topic>Interleukin-6 - genetics</topic><topic>Ligands</topic><topic>Lipopolysaccharide Receptors - metabolism</topic><topic>Male</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>NF-kappa B - metabolism</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Recombinant Proteins - metabolism</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction</topic><topic>Toll-Like Receptor 2 - metabolism</topic><topic>Toll-Like Receptor 4 - immunology</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Se-Chan</creatorcontrib><creatorcontrib>Stice, James P</creatorcontrib><creatorcontrib>Chen, Le</creatorcontrib><creatorcontrib>Jung, James S</creatorcontrib><creatorcontrib>Gupta, Sanjiv</creatorcontrib><creatorcontrib>Wang, Yin</creatorcontrib><creatorcontrib>Baumgarten, Georg</creatorcontrib><creatorcontrib>Trial, Joann</creatorcontrib><creatorcontrib>Knowlton, Anne A</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Se-Chan</au><au>Stice, James P</au><au>Chen, Le</au><au>Jung, James S</au><au>Gupta, Sanjiv</au><au>Wang, Yin</au><au>Baumgarten, Georg</au><au>Trial, Joann</au><au>Knowlton, Anne A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2009-12-04</date><risdate>2009</risdate><volume>105</volume><issue>12</issue><spage>1186</spage><epage>1195</epage><pages>1186-1195</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><abstract>RATIONALE:Previously, we have found that changes in the location of intracellular heat shock protein (HSP)60 are associated with apoptosis. HSP60 has been reported to be a ligand of Toll-like receptor (TLR)-4.
OBJECTIVE:We hypothesized that extracellular HSP60 (exHSP60) would mediate apoptosis via TLR4.
METHODS AND RESULTS:Adult rat cardiac myocytes were treated with HSP60, either recombinant human or with HSP60 purified from the media of injured rat cardiac myocytes. ExHSP60 induced apoptosis in cardiac myocytes, as detected by increased caspase 3 activity and increased DNA fragmentation. Apoptosis could be reduced by blocking antibodies to TLR4 and by nuclear factor κB binding decoys, but not completely inhibited, even though similar treatment blocked lipopolysaccharide-induced apoptosis. Three distinct controls showed no evidence for involvement of a ligand other than exHSP60 in the mediation of apoptosis.
CONCLUSIONS:This is the first report of HSP60-induced apoptosis via the TLRs. HSP60-mediated activation of TLR4 may be a mechanism of myocyte loss in heart failure, where HSP60 has been detected in the plasma.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>19875724</pmid><doi>10.1161/CIRCRESAHA.109.209643</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Heart Association Journals; EZB-FREE-00999 freely available EZB journals; Journals@Ovid Complete |
| subjects | Animals Antibodies Apoptosis Caspase 3 - metabolism Chaperonin 60 - metabolism DNA Fragmentation Endotoxins - metabolism HSP27 Heat-Shock Proteins - metabolism Humans Interleukin-1beta - genetics Interleukin-6 - genetics Ligands Lipopolysaccharide Receptors - metabolism Male Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology NF-kappa B - metabolism p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Rats Rats, Sprague-Dawley Recombinant Proteins - metabolism RNA, Messenger - metabolism Signal Transduction Toll-Like Receptor 2 - metabolism Toll-Like Receptor 4 - immunology Toll-Like Receptor 4 - metabolism Tumor Necrosis Factor-alpha - genetics |
| title | Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis |
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