A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice
A naturally-occurring mutation in cardiac calsequestrin (CASQ2) at amino acid 307 was discovered in a highly inbred family and hypothesized to cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The goal of this study was to establish a causal link between CASQ2(D307H) and the CPVT p...
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| Veröffentlicht in: | Cardiovascular research 2007-07, Vol.75 (1), p.69-78 |
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| creator | DIRKSEN, Wessel P LACOMBE, Veronique A CAMES, Cynthia A FRANZINI-ARMSTRONG, Clara GYÖRKE, Sandor PERIASAMY, Muthu MEI CHI KALYANASUNDARAM, Anuradha VIATCHENKO -KARPINSKI, Serge TERENTYEV, Dmitry ZHIXIANG ZHOU VEDAMOORTHYRAO, Srikanth NING LIE CHIAMVIMONVAT, Nipavan |
| description | A naturally-occurring mutation in cardiac calsequestrin (CASQ2) at amino acid 307 was discovered in a highly inbred family and hypothesized to cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The goal of this study was to establish a causal link between CASQ2(D307H) and the CPVT phenotype using an in vivo model.
Cardiac-specific expression of the CASQ2(D307H) transgene was achieved using the alpha-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2(D307H) from 2- to 6-fold possess structurally normal hearts without any sign of hypertrophy. The hearts displayed normal ventricular function. Myocytes isolated from TG mice had diminished I(Ca)-induced Ca2+ transient amplitude and duration, as well as increased Ca2+ spark frequency. These myocytes, when exposed to isoproterenol and caffeine, displayed disturbances in their rhythmic Ca2+ oscillations and membrane potential, and delayed afterdepolarizations. ECG monitoring revealed that TG mice challenged with isoproterenol and caffeine developed complex ventricular arrhythmias, including non-sustained polymorphic ventricular tachycardia.
The findings of the present study demonstrate that expression of mutant CASQ2(D307H) in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients. |
| doi_str_mv | 10.1016/j.cardiores.2007.03.002 |
| format | Article |
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Cardiac-specific expression of the CASQ2(D307H) transgene was achieved using the alpha-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2(D307H) from 2- to 6-fold possess structurally normal hearts without any sign of hypertrophy. The hearts displayed normal ventricular function. Myocytes isolated from TG mice had diminished I(Ca)-induced Ca2+ transient amplitude and duration, as well as increased Ca2+ spark frequency. These myocytes, when exposed to isoproterenol and caffeine, displayed disturbances in their rhythmic Ca2+ oscillations and membrane potential, and delayed afterdepolarizations. ECG monitoring revealed that TG mice challenged with isoproterenol and caffeine developed complex ventricular arrhythmias, including non-sustained polymorphic ventricular tachycardia.
The findings of the present study demonstrate that expression of mutant CASQ2(D307H) in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1016/j.cardiores.2007.03.002</identifier><identifier>PMID: 17449018</identifier><identifier>CODEN: CVREAU</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Animals ; Biological and medical sciences ; Caffeine - pharmacology ; Calcium - metabolism ; Calcium Signaling ; Calsequestrin - genetics ; Cardiac dysrhythmias ; Cardiology. Vascular system ; Cardiotonic Agents - pharmacology ; Death, Sudden, Cardiac - etiology ; Electrocardiography ; Heart ; Isoproterenol - pharmacology ; Medical sciences ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Models, Animal ; Mutation, Missense ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Sarcoplasmic Reticulum - metabolism ; Tachycardia, Ventricular - genetics ; Tachycardia, Ventricular - metabolism ; Tachycardia, Ventricular - pathology</subject><ispartof>Cardiovascular research, 2007-07, Vol.75 (1), p.69-78</ispartof><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2902-b86cde8a73e46eb15f8429f08e837a998b5af9ca79d7d5bfd5e4c2b4b8e727ed3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,778,782,883,27911,27912</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18847129$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17449018$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DIRKSEN, Wessel P</creatorcontrib><creatorcontrib>LACOMBE, Veronique A</creatorcontrib><creatorcontrib>CAMES, Cynthia A</creatorcontrib><creatorcontrib>FRANZINI-ARMSTRONG, Clara</creatorcontrib><creatorcontrib>GYÖRKE, Sandor</creatorcontrib><creatorcontrib>PERIASAMY, Muthu</creatorcontrib><creatorcontrib>MEI CHI</creatorcontrib><creatorcontrib>KALYANASUNDARAM, Anuradha</creatorcontrib><creatorcontrib>VIATCHENKO -KARPINSKI, Serge</creatorcontrib><creatorcontrib>TERENTYEV, Dmitry</creatorcontrib><creatorcontrib>ZHIXIANG ZHOU</creatorcontrib><creatorcontrib>VEDAMOORTHYRAO, Srikanth</creatorcontrib><creatorcontrib>NING LIE</creatorcontrib><creatorcontrib>CHIAMVIMONVAT, Nipavan</creatorcontrib><title>A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>A naturally-occurring mutation in cardiac calsequestrin (CASQ2) at amino acid 307 was discovered in a highly inbred family and hypothesized to cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The goal of this study was to establish a causal link between CASQ2(D307H) and the CPVT phenotype using an in vivo model.
Cardiac-specific expression of the CASQ2(D307H) transgene was achieved using the alpha-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2(D307H) from 2- to 6-fold possess structurally normal hearts without any sign of hypertrophy. The hearts displayed normal ventricular function. Myocytes isolated from TG mice had diminished I(Ca)-induced Ca2+ transient amplitude and duration, as well as increased Ca2+ spark frequency. These myocytes, when exposed to isoproterenol and caffeine, displayed disturbances in their rhythmic Ca2+ oscillations and membrane potential, and delayed afterdepolarizations. ECG monitoring revealed that TG mice challenged with isoproterenol and caffeine developed complex ventricular arrhythmias, including non-sustained polymorphic ventricular tachycardia.
The findings of the present study demonstrate that expression of mutant CASQ2(D307H) in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Caffeine - pharmacology</subject><subject>Calcium - metabolism</subject><subject>Calcium Signaling</subject><subject>Calsequestrin - genetics</subject><subject>Cardiac dysrhythmias</subject><subject>Cardiology. Vascular system</subject><subject>Cardiotonic Agents - pharmacology</subject><subject>Death, Sudden, Cardiac - etiology</subject><subject>Electrocardiography</subject><subject>Heart</subject><subject>Isoproterenol - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microscopy, Confocal</subject><subject>Models, Animal</subject><subject>Mutation, Missense</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Sarcoplasmic Reticulum - metabolism</subject><subject>Tachycardia, Ventricular - genetics</subject><subject>Tachycardia, Ventricular - metabolism</subject><subject>Tachycardia, Ventricular - pathology</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkdtu1DAQhi0EokvhFcA3cEMTxnYcOzdIq-VQpEoICtfWxHG6XuVUO6noG_DYOHTVwtXI8j_fjOYj5BWDnAEr3x1yi6HxY3Ax5wAqB5ED8Edkw5SUmeCFfEw2AKCzUpTihDyL8ZCeUqriKTlhqigqYHpDfm9pv8w4-3GgfqAWu-iuFxfn4IczuttefuMfBKjzM-r7CX2I9BKDHacOY-8t_e5mb5du6ekO-Vu6x6Hp_HBFU02sJbpI7dhPnftFb9yQoCmMgWII-9t533uM69REcs_Jk3Yd_uJYT8nPTx9_7M6zi6-fv-y2F5nlFfCs1qVtnEYlXFG6mslWF7xqQTstFFaVriW2lUVVNaqRddtIV1heF7V2iivXiFPy_o47LXXvGrtuhZ2Zgu8x3JoRvfn_Z_B7czXeGK6YAqgS4M0REMa_lzK9j9Z1HQ5uXKJRUDLGSpmC6i5owxhjcO39EAZmtWgO5t6iWS0aECZZTJ0v_93xoe-oLQVeHwMYk7I24GB9fMhpXSjGK_EHUD6sYA</recordid><startdate>20070701</startdate><enddate>20070701</enddate><creator>DIRKSEN, Wessel P</creator><creator>LACOMBE, Veronique A</creator><creator>CAMES, Cynthia A</creator><creator>FRANZINI-ARMSTRONG, Clara</creator><creator>GYÖRKE, Sandor</creator><creator>PERIASAMY, Muthu</creator><creator>MEI CHI</creator><creator>KALYANASUNDARAM, Anuradha</creator><creator>VIATCHENKO -KARPINSKI, Serge</creator><creator>TERENTYEV, Dmitry</creator><creator>ZHIXIANG ZHOU</creator><creator>VEDAMOORTHYRAO, Srikanth</creator><creator>NING LIE</creator><creator>CHIAMVIMONVAT, Nipavan</creator><general>Oxford University Press</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20070701</creationdate><title>A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice</title><author>DIRKSEN, Wessel P ; LACOMBE, Veronique A ; CAMES, Cynthia A ; FRANZINI-ARMSTRONG, Clara ; GYÖRKE, Sandor ; PERIASAMY, Muthu ; MEI CHI ; KALYANASUNDARAM, Anuradha ; VIATCHENKO -KARPINSKI, Serge ; TERENTYEV, Dmitry ; ZHIXIANG ZHOU ; VEDAMOORTHYRAO, Srikanth ; NING LIE ; CHIAMVIMONVAT, Nipavan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2902-b86cde8a73e46eb15f8429f08e837a998b5af9ca79d7d5bfd5e4c2b4b8e727ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Caffeine - pharmacology</topic><topic>Calcium - metabolism</topic><topic>Calcium Signaling</topic><topic>Calsequestrin - genetics</topic><topic>Cardiac dysrhythmias</topic><topic>Cardiology. Vascular system</topic><topic>Cardiotonic Agents - pharmacology</topic><topic>Death, Sudden, Cardiac - etiology</topic><topic>Electrocardiography</topic><topic>Heart</topic><topic>Isoproterenol - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microscopy, Confocal</topic><topic>Models, Animal</topic><topic>Mutation, Missense</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Sarcoplasmic Reticulum - metabolism</topic><topic>Tachycardia, Ventricular - genetics</topic><topic>Tachycardia, Ventricular - metabolism</topic><topic>Tachycardia, Ventricular - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DIRKSEN, Wessel P</creatorcontrib><creatorcontrib>LACOMBE, Veronique A</creatorcontrib><creatorcontrib>CAMES, Cynthia A</creatorcontrib><creatorcontrib>FRANZINI-ARMSTRONG, Clara</creatorcontrib><creatorcontrib>GYÖRKE, Sandor</creatorcontrib><creatorcontrib>PERIASAMY, Muthu</creatorcontrib><creatorcontrib>MEI CHI</creatorcontrib><creatorcontrib>KALYANASUNDARAM, Anuradha</creatorcontrib><creatorcontrib>VIATCHENKO -KARPINSKI, Serge</creatorcontrib><creatorcontrib>TERENTYEV, Dmitry</creatorcontrib><creatorcontrib>ZHIXIANG ZHOU</creatorcontrib><creatorcontrib>VEDAMOORTHYRAO, Srikanth</creatorcontrib><creatorcontrib>NING LIE</creatorcontrib><creatorcontrib>CHIAMVIMONVAT, Nipavan</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DIRKSEN, Wessel P</au><au>LACOMBE, Veronique A</au><au>CAMES, Cynthia A</au><au>FRANZINI-ARMSTRONG, Clara</au><au>GYÖRKE, Sandor</au><au>PERIASAMY, Muthu</au><au>MEI CHI</au><au>KALYANASUNDARAM, Anuradha</au><au>VIATCHENKO -KARPINSKI, Serge</au><au>TERENTYEV, Dmitry</au><au>ZHIXIANG ZHOU</au><au>VEDAMOORTHYRAO, Srikanth</au><au>NING LIE</au><au>CHIAMVIMONVAT, Nipavan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2007-07-01</date><risdate>2007</risdate><volume>75</volume><issue>1</issue><spage>69</spage><epage>78</epage><pages>69-78</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><coden>CVREAU</coden><abstract>A naturally-occurring mutation in cardiac calsequestrin (CASQ2) at amino acid 307 was discovered in a highly inbred family and hypothesized to cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The goal of this study was to establish a causal link between CASQ2(D307H) and the CPVT phenotype using an in vivo model.
Cardiac-specific expression of the CASQ2(D307H) transgene was achieved using the alpha-MHC promoter. Multiple transgenic (TG) mouse lines expressing CASQ2(D307H) from 2- to 6-fold possess structurally normal hearts without any sign of hypertrophy. The hearts displayed normal ventricular function. Myocytes isolated from TG mice had diminished I(Ca)-induced Ca2+ transient amplitude and duration, as well as increased Ca2+ spark frequency. These myocytes, when exposed to isoproterenol and caffeine, displayed disturbances in their rhythmic Ca2+ oscillations and membrane potential, and delayed afterdepolarizations. ECG monitoring revealed that TG mice challenged with isoproterenol and caffeine developed complex ventricular arrhythmias, including non-sustained polymorphic ventricular tachycardia.
The findings of the present study demonstrate that expression of mutant CASQ2(D307H) in the mouse heart results in abnormal myocyte Ca2+ handling and predisposes to complex ventricular arrhythmias similar to the CPVT phenotype observed in human patients.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>17449018</pmid><doi>10.1016/j.cardiores.2007.03.002</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Animals Biological and medical sciences Caffeine - pharmacology Calcium - metabolism Calcium Signaling Calsequestrin - genetics Cardiac dysrhythmias Cardiology. Vascular system Cardiotonic Agents - pharmacology Death, Sudden, Cardiac - etiology Electrocardiography Heart Isoproterenol - pharmacology Medical sciences Mice Mice, Transgenic Microscopy, Confocal Models, Animal Mutation, Missense Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Sarcoplasmic Reticulum - metabolism Tachycardia, Ventricular - genetics Tachycardia, Ventricular - metabolism Tachycardia, Ventricular - pathology |
| title | A mutation in calsequestrin, CASQ2D307H, impairs Sarcoplasmic Reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice |
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