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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Perturbed Length–Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations</title><author><name sortKey="Sequeira, Vasco" sort="Sequeira, Vasco" uniqKey="Sequeira V" first="Vasco" last="Sequeira">Vasco Sequeira</name></author><author><name sortKey="Wijnker, Paul J M" sort="Wijnker, Paul J M" uniqKey="Wijnker P" first="Paul J. M." last="Wijnker">Paul J. M. Wijnker</name></author><author><name sortKey="Nijenkamp, Louise L A M" sort="Nijenkamp, Louise L A M" uniqKey="Nijenkamp L" first="Louise L. A. M." last="Nijenkamp">Louise L. A. M. Nijenkamp</name></author><author><name sortKey="Kuster, Diederik W D" sort="Kuster, Diederik W D" uniqKey="Kuster D" first="Diederik W. D." last="Kuster">Diederik W. D. Kuster</name></author><author><name sortKey="Najafi, Aref" sort="Najafi, Aref" uniqKey="Najafi A" first="Aref" last="Najafi">Aref Najafi</name></author><author><name sortKey="Witjas Paalberends, E Rosalie" sort="Witjas Paalberends, E Rosalie" uniqKey="Witjas Paalberends E" first="E. Rosalie" last="Witjas-Paalberends">E. Rosalie Witjas-Paalberends</name></author><author><name sortKey="Regan, Jessica A" sort="Regan, Jessica A" uniqKey="Regan J" first="Jessica A." last="Regan">Jessica A. Regan</name></author><author><name sortKey="Boontje, Nicky" sort="Boontje, Nicky" uniqKey="Boontje N" first="Nicky" last="Boontje">Nicky Boontje</name></author><author><name sortKey="Ten Cate, Folkert J" sort="Ten Cate, Folkert J" uniqKey="Ten Cate F" first="Folkert J." last="Ten Cate">Folkert J. Ten Cate</name></author><author><name sortKey="Germans, Tjeerd" sort="Germans, Tjeerd" uniqKey="Germans T" first="Tjeerd" last="Germans">Tjeerd Germans</name></author><author><name sortKey="Carrier, Lucie" sort="Carrier, Lucie" uniqKey="Carrier L" first="Lucie" last="Carrier">Lucie Carrier</name></author><author><name sortKey="Sadayappan, Sakthivel" sort="Sadayappan, Sakthivel" uniqKey="Sadayappan S" first="Sakthivel" last="Sadayappan">Sakthivel Sadayappan</name></author><author><name sortKey="Van Slegtenhorst, Marjon A" sort="Van Slegtenhorst, Marjon A" uniqKey="Van Slegtenhorst M" first="Marjon A." last="Van Slegtenhorst">Marjon A. Van Slegtenhorst</name></author><author><name sortKey="Zaremba, Ruud" sort="Zaremba, Ruud" uniqKey="Zaremba R" first="Ruud" last="Zaremba">Ruud Zaremba</name></author><author><name sortKey="Foster, D Brian" sort="Foster, D Brian" uniqKey="Foster D" first="D. Brian" last="Foster">D. Brian Foster</name></author><author><name sortKey="Murphy, Anne M" sort="Murphy, Anne M" uniqKey="Murphy A" first="Anne M." last="Murphy">Anne M. Murphy</name></author><author><name sortKey="Poggesi, Corrado" sort="Poggesi, Corrado" uniqKey="Poggesi C" first="Corrado" last="Poggesi">Corrado Poggesi</name></author><author><name sortKey="Dos Remedios, Cris" sort="Dos Remedios, Cris" uniqKey="Dos Remedios C" first="Cris" last="Dos Remedios">Cris Dos Remedios</name></author><author><name sortKey="Stienen, Ger J M" sort="Stienen, Ger J M" uniqKey="Stienen G" first="Ger J. M." last="Stienen">Ger J. M. Stienen</name></author><author><name sortKey="Ho, Carolyn Y" sort="Ho, Carolyn Y" uniqKey="Ho C" first="Carolyn Y." last="Ho">Carolyn Y. Ho</name></author><author><name sortKey="Michels, Michelle" sort="Michels, Michelle" uniqKey="Michels M" first="Michelle" last="Michels">Michelle Michels</name></author><author><name sortKey="Van Der Velden, Jolanda" sort="Van Der Velden, Jolanda" uniqKey="Van Der Velden J" first="Jolanda" last="Van Der Velden">Jolanda Van Der Velden</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23508784</idno><idno type="pmc">3675884</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675884</idno><idno type="RBID">PMC:3675884</idno><idno type="doi">10.1161/CIRCRESAHA.111.300436</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">001C63</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001C63</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Perturbed Length–Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations</title><author><name sortKey="Sequeira, Vasco" sort="Sequeira, Vasco" uniqKey="Sequeira V" first="Vasco" last="Sequeira">Vasco Sequeira</name></author><author><name sortKey="Wijnker, Paul J M" sort="Wijnker, Paul J M" uniqKey="Wijnker P" first="Paul J. M." last="Wijnker">Paul J. M. Wijnker</name></author><author><name sortKey="Nijenkamp, Louise L A M" sort="Nijenkamp, Louise L A M" uniqKey="Nijenkamp L" first="Louise L. A. M." last="Nijenkamp">Louise L. A. M. Nijenkamp</name></author><author><name sortKey="Kuster, Diederik W D" sort="Kuster, Diederik W D" uniqKey="Kuster D" first="Diederik W. D." last="Kuster">Diederik W. D. Kuster</name></author><author><name sortKey="Najafi, Aref" sort="Najafi, Aref" uniqKey="Najafi A" first="Aref" last="Najafi">Aref Najafi</name></author><author><name sortKey="Witjas Paalberends, E Rosalie" sort="Witjas Paalberends, E Rosalie" uniqKey="Witjas Paalberends E" first="E. Rosalie" last="Witjas-Paalberends">E. Rosalie Witjas-Paalberends</name></author><author><name sortKey="Regan, Jessica A" sort="Regan, Jessica A" uniqKey="Regan J" first="Jessica A." last="Regan">Jessica A. Regan</name></author><author><name sortKey="Boontje, Nicky" sort="Boontje, Nicky" uniqKey="Boontje N" first="Nicky" last="Boontje">Nicky Boontje</name></author><author><name sortKey="Ten Cate, Folkert J" sort="Ten Cate, Folkert J" uniqKey="Ten Cate F" first="Folkert J." last="Ten Cate">Folkert J. Ten Cate</name></author><author><name sortKey="Germans, Tjeerd" sort="Germans, Tjeerd" uniqKey="Germans T" first="Tjeerd" last="Germans">Tjeerd Germans</name></author><author><name sortKey="Carrier, Lucie" sort="Carrier, Lucie" uniqKey="Carrier L" first="Lucie" last="Carrier">Lucie Carrier</name></author><author><name sortKey="Sadayappan, Sakthivel" sort="Sadayappan, Sakthivel" uniqKey="Sadayappan S" first="Sakthivel" last="Sadayappan">Sakthivel Sadayappan</name></author><author><name sortKey="Van Slegtenhorst, Marjon A" sort="Van Slegtenhorst, Marjon A" uniqKey="Van Slegtenhorst M" first="Marjon A." last="Van Slegtenhorst">Marjon A. Van Slegtenhorst</name></author><author><name sortKey="Zaremba, Ruud" sort="Zaremba, Ruud" uniqKey="Zaremba R" first="Ruud" last="Zaremba">Ruud Zaremba</name></author><author><name sortKey="Foster, D Brian" sort="Foster, D Brian" uniqKey="Foster D" first="D. Brian" last="Foster">D. Brian Foster</name></author><author><name sortKey="Murphy, Anne M" sort="Murphy, Anne M" uniqKey="Murphy A" first="Anne M." last="Murphy">Anne M. Murphy</name></author><author><name sortKey="Poggesi, Corrado" sort="Poggesi, Corrado" uniqKey="Poggesi C" first="Corrado" last="Poggesi">Corrado Poggesi</name></author><author><name sortKey="Dos Remedios, Cris" sort="Dos Remedios, Cris" uniqKey="Dos Remedios C" first="Cris" last="Dos Remedios">Cris Dos Remedios</name></author><author><name sortKey="Stienen, Ger J M" sort="Stienen, Ger J M" uniqKey="Stienen G" first="Ger J. M." last="Stienen">Ger J. M. Stienen</name></author><author><name sortKey="Ho, Carolyn Y" sort="Ho, Carolyn Y" uniqKey="Ho C" first="Carolyn Y." last="Ho">Carolyn Y. Ho</name></author><author><name sortKey="Michels, Michelle" sort="Michels, Michelle" uniqKey="Michels M" first="Michelle" last="Michels">Michelle Michels</name></author><author><name sortKey="Van Der Velden, Jolanda" sort="Van Der Velden, Jolanda" uniqKey="Van Der Velden J" first="Jolanda" last="Van Der Velden">Jolanda Van Der Velden</name></author></analytic><series><title level="j">Circulation research</title><idno type="ISSN">0009-7330</idno><idno type="eISSN">1524-4571</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Rationale</title><p id="P1">High-myofilament Ca<sup>2+</sup>-sensitivity has been proposed as trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) based on in vitro and transgenic mice studies. However, myofilament Ca<sup>2+</sup>-sensitivity depends on protein phosphorylation and muscle length, and at present, data in human are scarce.</p></sec><sec id="S2"><title>Objective</title><p id="P2">To investigate whether high-myofilament Ca<sup>2+</sup>-sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick- and thin-filament proteins.</p></sec><sec id="S3"><title>Methods and Results</title><p id="P3">Cardiac samples from patients with HCM harboring mutations in genes encoding thick (<italic>MYH7</italic>, <italic>MYBPC3</italic>) and thin (<italic>TNNT2</italic>, <italic>TNNI3</italic>, <italic>TPM1</italic>) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca<sup>2+</sup>-sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA)-targets compared with donors. After exogenous PKA treatment, myofilament Ca<sup>2+</sup>-sensitivity was either similar (<italic>MYBPC3</italic><sub>mut</sub>, <italic>TPM1</italic><sub>mut</sub>, sarcomere mutation-negative HCM), higher (<italic>MYH7</italic><sub>mut</sub>, <italic>TNNT2</italic><sub>mut</sub>), or even significantly lower (<italic>TNNI3</italic><sub>mut</sub>) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating <italic>MYBPC3</italic> mutations, but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in <italic>TNNT2</italic><sub>mut</sub> and <italic>TNNI3</italic><sub>mut</sub> corrected length-dependent activation to donor values.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">High-myofilament Ca<sup>2+</sup>-sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA-targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via post-translational modifications other than PKA-hypophosphorylation or altered protein–protein interactions, and represents a common pathomechanism in HCM.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0047103</journal-id><journal-id journal-id-type="pubmed-jr-id">2974</journal-id><journal-id journal-id-type="nlm-ta">Circ Res</journal-id><journal-id journal-id-type="iso-abbrev">Circ. Res.</journal-id><journal-title-group><journal-title>Circulation research</journal-title></journal-title-group><issn pub-type="ppub">0009-7330</issn><issn pub-type="epub">1524-4571</issn></journal-meta><article-meta><article-id pub-id-type="pmid">23508784</article-id><article-id pub-id-type="pmc">3675884</article-id><article-id pub-id-type="doi">10.1161/CIRCRESAHA.111.300436</article-id><article-id pub-id-type="manuscript">NIHMS470681</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Perturbed Length–Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Sequeira</surname><given-names>Vasco</given-names></name><xref rid="FN2" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Wijnker</surname><given-names>Paul J.M.</given-names></name><xref rid="FN2" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Nijenkamp</surname><given-names>Louise L.A.M.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Kuster</surname><given-names>Diederik W.D.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Najafi</surname><given-names>Aref</given-names></name></contrib><contrib contrib-type="author"><name><surname>Witjas-Paalberends</surname><given-names>E. Rosalie</given-names></name></contrib><contrib contrib-type="author"><name><surname>Regan</surname><given-names>Jessica A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Boontje</surname><given-names>Nicky</given-names></name></contrib><contrib contrib-type="author"><name><surname>ten Cate</surname><given-names>Folkert J.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Germans</surname><given-names>Tjeerd</given-names></name></contrib><contrib contrib-type="author"><name><surname>Carrier</surname><given-names>Lucie</given-names></name></contrib><contrib contrib-type="author"><name><surname>Sadayappan</surname><given-names>Sakthivel</given-names></name></contrib><contrib contrib-type="author"><name><surname>van Slegtenhorst</surname><given-names>Marjon A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Zaremba</surname><given-names>Ruud</given-names></name></contrib><contrib contrib-type="author"><name><surname>Foster</surname><given-names>D. Brian</given-names></name></contrib><contrib contrib-type="author"><name><surname>Murphy</surname><given-names>Anne M.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Poggesi</surname><given-names>Corrado</given-names></name></contrib><contrib contrib-type="author"><name><surname>dos Remedios</surname><given-names>Cris</given-names></name></contrib><contrib contrib-type="author"><name><surname>Stienen</surname><given-names>Ger J.M.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Ho</surname><given-names>Carolyn Y.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Michels</surname><given-names>Michelle</given-names></name></contrib><contrib contrib-type="author"><name><surname>van der Velden</surname><given-names>Jolanda</given-names></name></contrib><aff id="A1">the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.), Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson, AZ (J.A.R.); Thorax Center, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands (F.J.t.C., M.A.v.S., M.M.); Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany, and DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (L.C.); UPMC Univ Paris, Paris, France (L.C.); Inserm U974, Institut de Myologie, Paris, France (L.C.); Division of Cardiology (D.B.F.) and Department of Pediatrics (A..M.M.), Johns Hopkins University School of Medicine, Baltimore, MD; Dipartimento di Scienze Fisiologiche, Università degli Studi di Firenze, Firenze, Italy (C.P.); Muscle Research Unit, Bosch Institute, University of Sydney, Sydney, Australia (C.d.R.); Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands (G.J.M.S.); Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.Y.H.); and ICIN- Netherlands Heart Institute, Utrecht, the Netherlands (J.v.d.V.)</aff></contrib-group><author-notes><corresp id="FN1">Correspondence to Dr Vasco Sequeira, Laboratory for Physiology, VU University Medical Center, Institute for Cardiovascular Research (ICaR-VU), van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands. <email>v.sequeiraoliveira@vumc.nl</email></corresp><fn id="FN2" fn-type="equal"><label>*</label><p>These authors contributed equally.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>22</day><month>5</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>18</day><month>3</month><year>2013</year></pub-date><pub-date pub-type="ppub"><day>24</day><month>5</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>24</day><month>5</month><year>2014</year></pub-date><volume>112</volume><issue>11</issue><fpage>1491</fpage><lpage>1505</lpage><abstract><sec id="S1"><title>Rationale</title><p id="P1">High-myofilament Ca<sup>2+</sup>-sensitivity has been proposed as trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) based on in vitro and transgenic mice studies. However, myofilament Ca<sup>2+</sup>-sensitivity depends on protein phosphorylation and muscle length, and at present, data in human are scarce.</p></sec><sec id="S2"><title>Objective</title><p id="P2">To investigate whether high-myofilament Ca<sup>2+</sup>-sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick- and thin-filament proteins.</p></sec><sec id="S3"><title>Methods and Results</title><p id="P3">Cardiac samples from patients with HCM harboring mutations in genes encoding thick (<italic>MYH7</italic>, <italic>MYBPC3</italic>) and thin (<italic>TNNT2</italic>, <italic>TNNI3</italic>, <italic>TPM1</italic>) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca<sup>2+</sup>-sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA)-targets compared with donors. After exogenous PKA treatment, myofilament Ca<sup>2+</sup>-sensitivity was either similar (<italic>MYBPC3</italic><sub>mut</sub>, <italic>TPM1</italic><sub>mut</sub>, sarcomere mutation-negative HCM), higher (<italic>MYH7</italic><sub>mut</sub>, <italic>TNNT2</italic><sub>mut</sub>), or even significantly lower (<italic>TNNI3</italic><sub>mut</sub>) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating <italic>MYBPC3</italic> mutations, but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in <italic>TNNT2</italic><sub>mut</sub> and <italic>TNNI3</italic><sub>mut</sub> corrected length-dependent activation to donor values.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">High-myofilament Ca<sup>2+</sup>-sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA-targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via post-translational modifications other than PKA-hypophosphorylation or altered protein–protein interactions, and represents a common pathomechanism in HCM.</p></sec></abstract><kwd-group><kwd>calcium</kwd><kwd>cardiomyopathy</kwd><kwd>contractility</kwd><kwd>hypertrophy</kwd><kwd>myocardium</kwd></kwd-group><funding-group><award-group><funding-source country="United States">National Heart, Lung, and Blood Institute : NHLBI</funding-source><award-id>R01 HL063038 || HL</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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