Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation
Objective:Recently, a clinical trial was initiated to evaluate the efficacy of transendocardial transplantation of autologous bone marrow-derived mesenchymal stem cells (MSC) for the treatment of heart failure (HF). Because some HF patient-derived sera did not induce proliferation of autologous MSC,...
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| Veröffentlicht in: | Heart (British Cardiac Society) 2009-02, Vol.95 (4), p.283-289 |
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| creator | Yamahara, K Min, K D Tomoike, H Kangawa, K Kitamura, S Nagaya, N |
| description | Objective:Recently, a clinical trial was initiated to evaluate the efficacy of transendocardial transplantation of autologous bone marrow-derived mesenchymal stem cells (MSC) for the treatment of heart failure (HF). Because some HF patient-derived sera did not induce proliferation of autologous MSC, the present study aimed to elucidate humoral factors in sera that attenuate MSC activation and to investigate the role of these humoral factors in the pathogenesis of HF.Methods and results:Inhibitory effects present in serum were analysed by culturing human MSC with sera from 10 HF patients (FS 100 pg/ml) and four healthy control subjects. Among the patients, two sera from HF patients showed significant inhibitory activity on MSC proliferation. Protein array and ELISA analysis revealed that these sera contained high levels of angiostatin as well as the active form of matrix metalloproteinase (MMP)-9, which generates angiostatin. Angiostatin significantly inhibited the proliferation and migration of cultured human MSC and increased their apoptosis in a dose-dependent manner. In a rat HF model, serum levels of angiostatin and MMPs increased, but treatment with an MMP inhibitor suppressed these increases.Conclusions:The results suggest that angiostatin, which can attenuate the activity of MSC, might play a role in the progression of HF. |
| doi_str_mv | 10.1136/hrt.2008.152223 |
| format | Article |
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Because some HF patient-derived sera did not induce proliferation of autologous MSC, the present study aimed to elucidate humoral factors in sera that attenuate MSC activation and to investigate the role of these humoral factors in the pathogenesis of HF.Methods and results:Inhibitory effects present in serum were analysed by culturing human MSC with sera from 10 HF patients (FS <25%, BNP >100 pg/ml) and four healthy control subjects. Among the patients, two sera from HF patients showed significant inhibitory activity on MSC proliferation. Protein array and ELISA analysis revealed that these sera contained high levels of angiostatin as well as the active form of matrix metalloproteinase (MMP)-9, which generates angiostatin. Angiostatin significantly inhibited the proliferation and migration of cultured human MSC and increased their apoptosis in a dose-dependent manner. In a rat HF model, serum levels of angiostatin and MMPs increased, but treatment with an MMP inhibitor suppressed these increases.Conclusions:The results suggest that angiostatin, which can attenuate the activity of MSC, might play a role in the progression of HF.</description><identifier>ISSN: 1355-6037</identifier><identifier>EISSN: 1468-201X</identifier><identifier>DOI: 10.1136/hrt.2008.152223</identifier><identifier>PMID: 19095709</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd and British Cardiovascular Society</publisher><subject>Angiostatins - blood ; Angiostatins - pharmacology ; Angiostatins - physiology ; Animals ; Antibiotics ; Apoptosis ; Apoptosis - drug effects ; Biological and medical sciences ; Cardiology. Vascular system ; Cardiomyopathy ; Cell Proliferation - drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay - methods ; Gangrene ; Heart ; Heart failure ; Heart Failure - blood ; Heart Failure - etiology ; Heart Failure - metabolism ; Heart failure, cardiogenic pulmonary edema, cardiac enlargement ; Humans ; Interleukin-6 - analysis ; Male ; Matrix Metalloproteinase 9 - analysis ; Matrix Metalloproteinase 9 - blood ; Matrix Metalloproteinase 9 - metabolism ; Medical sciences ; Mesenchymal Stromal Cells - drug effects ; Mesenchymal Stromal Cells - physiology ; Protein Array Analysis ; Proteins ; Rats ; Rats, Inbred Lew ; Studies ; Tumor Necrosis Factor-alpha - analysis ; Tumor necrosis factor-TNF</subject><ispartof>Heart (British Cardiac Society), 2009-02, Vol.95 (4), p.283-289</ispartof><rights>2009 BMJ Publishing Group and British Cardiac Society</rights><rights>2009 INIST-CNRS</rights><rights>Copyright: 2009 2009 BMJ Publishing Group and British Cardiac Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b426t-48c4f770a614806a988a071570cbfa6f3b612251c6ef5d5eb5dc34501237eac23</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttp://heart.bmj.com/content/95/4/283.full.pdf$$EPDF$$P50$$Gbmj$$H</linktopdf><linktohtml>$$Uhttp://heart.bmj.com/content/95/4/283.full$$EHTML$$P50$$Gbmj$$H</linktohtml><link.rule.ids>114,115,314,776,780,3183,23550,27901,27902,77343,77374</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21121148$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19095709$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamahara, K</creatorcontrib><creatorcontrib>Min, K D</creatorcontrib><creatorcontrib>Tomoike, H</creatorcontrib><creatorcontrib>Kangawa, K</creatorcontrib><creatorcontrib>Kitamura, S</creatorcontrib><creatorcontrib>Nagaya, N</creatorcontrib><title>Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation</title><title>Heart (British Cardiac Society)</title><addtitle>Heart</addtitle><description>Objective:Recently, a clinical trial was initiated to evaluate the efficacy of transendocardial transplantation of autologous bone marrow-derived mesenchymal stem cells (MSC) for the treatment of heart failure (HF). Because some HF patient-derived sera did not induce proliferation of autologous MSC, the present study aimed to elucidate humoral factors in sera that attenuate MSC activation and to investigate the role of these humoral factors in the pathogenesis of HF.Methods and results:Inhibitory effects present in serum were analysed by culturing human MSC with sera from 10 HF patients (FS <25%, BNP >100 pg/ml) and four healthy control subjects. Among the patients, two sera from HF patients showed significant inhibitory activity on MSC proliferation. Protein array and ELISA analysis revealed that these sera contained high levels of angiostatin as well as the active form of matrix metalloproteinase (MMP)-9, which generates angiostatin. Angiostatin significantly inhibited the proliferation and migration of cultured human MSC and increased their apoptosis in a dose-dependent manner. In a rat HF model, serum levels of angiostatin and MMPs increased, but treatment with an MMP inhibitor suppressed these increases.Conclusions:The results suggest that angiostatin, which can attenuate the activity of MSC, might play a role in the progression of HF.</description><subject>Angiostatins - blood</subject><subject>Angiostatins - pharmacology</subject><subject>Angiostatins - physiology</subject><subject>Animals</subject><subject>Antibiotics</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Cardiomyopathy</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme-Linked Immunosorbent Assay - methods</subject><subject>Gangrene</subject><subject>Heart</subject><subject>Heart failure</subject><subject>Heart Failure - blood</subject><subject>Heart Failure - etiology</subject><subject>Heart Failure - metabolism</subject><subject>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</subject><subject>Humans</subject><subject>Interleukin-6 - analysis</subject><subject>Male</subject><subject>Matrix Metalloproteinase 9 - analysis</subject><subject>Matrix Metalloproteinase 9 - blood</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Medical sciences</subject><subject>Mesenchymal Stromal Cells - drug effects</subject><subject>Mesenchymal Stromal Cells - physiology</subject><subject>Protein Array Analysis</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>Studies</subject><subject>Tumor Necrosis Factor-alpha - analysis</subject><subject>Tumor necrosis factor-TNF</subject><issn>1355-6037</issn><issn>1468-201X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkc9rFDEcxYMotlbP3mRA9CDMNslMfkxvutUqlOpBq3gJmWyyk3UmqUlG7H_vd5mlghchkMD38315vIfQU4JXhDT8dEhlRTGWK8Iopc09dExaLmuKybf78G4YqzluxBF6lPMOY9x2kj9ER6TDHRO4O0bhky5DHOPWGz1WKY62iq7SYetjLrr4UMEZrE6lctqPc7JnMK1s2MStDXHOMB9870tM-8XJZhvMcDuBWC52qo0dx0qb4n-BWAyP0QOnx2yfHO4T9OXd28_r9_Xlx4sP69eXdd9SXupWmtYJgTUnrcRcd1JqLAhYNr3T3DU9J5QyYrh1bMNszzamaRkmtBFWG9qcoJeL7k2KP2ebi5p83nvRwYJpxbnkEBkH8Pk_4C7OKYA3RQR83bUdJkCdLpRJMedknbpJftLpVhGs9kUoKELti1BLEbDx7KA795Pd_OUPyQPw4gDoDNG7pIPx-Y6jhMBpJXD1wnnI8_fdXKcfiotGMHV1vVbnX6_enK-vv6sL4F8tfD_t_uvyD_kVrcc</recordid><startdate>20090201</startdate><enddate>20090201</enddate><creator>Yamahara, K</creator><creator>Min, K D</creator><creator>Tomoike, H</creator><creator>Kangawa, K</creator><creator>Kitamura, S</creator><creator>Nagaya, N</creator><general>BMJ Publishing Group Ltd and British Cardiovascular Society</general><general>BMJ Publishing Group</general><general>BMJ Publishing Group LTD</general><scope>BSCLL</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20090201</creationdate><title>Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation</title><author>Yamahara, K ; Min, K D ; Tomoike, H ; Kangawa, K ; Kitamura, S ; Nagaya, N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b426t-48c4f770a614806a988a071570cbfa6f3b612251c6ef5d5eb5dc34501237eac23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Angiostatins - blood</topic><topic>Angiostatins - pharmacology</topic><topic>Angiostatins - physiology</topic><topic>Animals</topic><topic>Antibiotics</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Cardiology. Vascular system</topic><topic>Cardiomyopathy</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme-Linked Immunosorbent Assay - methods</topic><topic>Gangrene</topic><topic>Heart</topic><topic>Heart failure</topic><topic>Heart Failure - blood</topic><topic>Heart Failure - etiology</topic><topic>Heart Failure - metabolism</topic><topic>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</topic><topic>Humans</topic><topic>Interleukin-6 - analysis</topic><topic>Male</topic><topic>Matrix Metalloproteinase 9 - analysis</topic><topic>Matrix Metalloproteinase 9 - blood</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Medical sciences</topic><topic>Mesenchymal Stromal Cells - drug effects</topic><topic>Mesenchymal Stromal Cells - physiology</topic><topic>Protein Array Analysis</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Inbred Lew</topic><topic>Studies</topic><topic>Tumor Necrosis Factor-alpha - analysis</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamahara, K</creatorcontrib><creatorcontrib>Min, K D</creatorcontrib><creatorcontrib>Tomoike, H</creatorcontrib><creatorcontrib>Kangawa, K</creatorcontrib><creatorcontrib>Kitamura, S</creatorcontrib><creatorcontrib>Nagaya, N</creatorcontrib><collection>Istex</collection><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>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</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>ProQuest Central</collection><collection>BMJ Journals</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>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science 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 Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Heart (British Cardiac Society)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamahara, K</au><au>Min, K D</au><au>Tomoike, H</au><au>Kangawa, K</au><au>Kitamura, S</au><au>Nagaya, N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation</atitle><jtitle>Heart (British Cardiac Society)</jtitle><addtitle>Heart</addtitle><date>2009-02-01</date><risdate>2009</risdate><volume>95</volume><issue>4</issue><spage>283</spage><epage>289</epage><pages>283-289</pages><issn>1355-6037</issn><eissn>1468-201X</eissn><abstract>Objective:Recently, a clinical trial was initiated to evaluate the efficacy of transendocardial transplantation of autologous bone marrow-derived mesenchymal stem cells (MSC) for the treatment of heart failure (HF). Because some HF patient-derived sera did not induce proliferation of autologous MSC, the present study aimed to elucidate humoral factors in sera that attenuate MSC activation and to investigate the role of these humoral factors in the pathogenesis of HF.Methods and results:Inhibitory effects present in serum were analysed by culturing human MSC with sera from 10 HF patients (FS <25%, BNP >100 pg/ml) and four healthy control subjects. Among the patients, two sera from HF patients showed significant inhibitory activity on MSC proliferation. Protein array and ELISA analysis revealed that these sera contained high levels of angiostatin as well as the active form of matrix metalloproteinase (MMP)-9, which generates angiostatin. Angiostatin significantly inhibited the proliferation and migration of cultured human MSC and increased their apoptosis in a dose-dependent manner. In a rat HF model, serum levels of angiostatin and MMPs increased, but treatment with an MMP inhibitor suppressed these increases.Conclusions:The results suggest that angiostatin, which can attenuate the activity of MSC, might play a role in the progression of HF.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd and British Cardiovascular Society</pub><pmid>19095709</pmid><doi>10.1136/hrt.2008.152223</doi><tpages>7</tpages></addata></record> |
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| subjects | Angiostatins - blood Angiostatins - pharmacology Angiostatins - physiology Animals Antibiotics Apoptosis Apoptosis - drug effects Biological and medical sciences Cardiology. Vascular system Cardiomyopathy Cell Proliferation - drug effects Cells, Cultured Dose-Response Relationship, Drug Enzyme-Linked Immunosorbent Assay - methods Gangrene Heart Heart failure Heart Failure - blood Heart Failure - etiology Heart Failure - metabolism Heart failure, cardiogenic pulmonary edema, cardiac enlargement Humans Interleukin-6 - analysis Male Matrix Metalloproteinase 9 - analysis Matrix Metalloproteinase 9 - blood Matrix Metalloproteinase 9 - metabolism Medical sciences Mesenchymal Stromal Cells - drug effects Mesenchymal Stromal Cells - physiology Protein Array Analysis Proteins Rats Rats, Inbred Lew Studies Tumor Necrosis Factor-alpha - analysis Tumor necrosis factor-TNF |
| title | Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation |
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