Protein Changes Contributing to Right Ventricular Cardiomyocyte Diastolic Dysfunction in Pulmonary Arterial Hypertension
Identifieur interne : 002477 ( Pmc/Curation ); précédent : 002476; suivant : 002478Protein Changes Contributing to Right Ventricular Cardiomyocyte Diastolic Dysfunction in Pulmonary Arterial Hypertension
Auteurs : Silvia Rain ; Denielli Da Silva Goncalves Bos ; M. Louis Handoko ; Nico Westerhof ; Ger Stienen ; Coen Ottenheijm ; Max Goebel ; Peter Dorfmüller ; Christophe Guignabert ; Marc Humbert ; Harm-Jan Bogaard ; Cris Dos Remedios ; Chandra Saripalli ; Carlos G. Hidalgo ; Henk L. Granzier ; Anton Vonk-Noordegraaf ; Jolanda Van Der Velden ; Frances S. De ManSource :
- Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease [ 2047-9980 ] ; 2014.
Abstract
Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca2+ sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH.
RV samples from PAH patients undergoing heart‐lung transplantation were compared to non‐failing donors (Don).
Increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca2+ handling proteins contribute to RV diastolic dysfunction in PAH.
Url:
DOI: 10.1161/JAHA.113.000716
PubMed: 24895160
PubMed Central: 4309054
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De Man</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24895160</idno><idno type="pmc">4309054</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309054</idno><idno type="RBID">PMC:4309054</idno><idno type="doi">10.1161/JAHA.113.000716</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">002627</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002627</idno><idno type="wicri:Area/Pmc/Curation">002477</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002477</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Protein Changes Contributing to Right Ventricular Cardiomyocyte Diastolic Dysfunction in Pulmonary Arterial Hypertension</title><author><name sortKey="Rain, Silvia" sort="Rain, Silvia" uniqKey="Rain S" first="Silvia" last="Rain">Silvia Rain</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Bos, Denielli Da Silva Goncalves" sort="Bos, Denielli Da Silva Goncalves" uniqKey="Bos D" first="Denielli Da Silva Goncalves" last="Bos">Denielli Da Silva Goncalves Bos</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Handoko, M Louis" sort="Handoko, M Louis" uniqKey="Handoko M" first="M. Louis" last="Handoko">M. Louis Handoko</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Westerhof, Nico" sort="Westerhof, Nico" uniqKey="Westerhof N" first="Nico" last="Westerhof">Nico Westerhof</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Stienen, Ger" sort="Stienen, Ger" uniqKey="Stienen G" first="Ger" last="Stienen">Ger Stienen</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Ottenheijm, Coen" sort="Ottenheijm, Coen" uniqKey="Ottenheijm C" first="Coen" last="Ottenheijm">Coen Ottenheijm</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Goebel, Max" sort="Goebel, Max" uniqKey="Goebel M" first="Max" last="Goebel">Max Goebel</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Dorfmuller, Peter" sort="Dorfmuller, Peter" uniqKey="Dorfmuller P" first="Peter" last="Dorfmüller">Peter Dorfmüller</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Guignabert, Christophe" sort="Guignabert, Christophe" uniqKey="Guignabert C" first="Christophe" last="Guignabert">Christophe Guignabert</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Humbert, Marc" sort="Humbert, Marc" uniqKey="Humbert M" first="Marc" last="Humbert">Marc Humbert</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Bogaard, Harm An" sort="Bogaard, Harm An" uniqKey="Bogaard H" first="Harm-Jan" last="Bogaard">Harm-Jan Bogaard</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Dos Remedios, Cris" sort="Dos Remedios, Cris" uniqKey="Dos Remedios C" first="Cris" last="Dos Remedios">Cris Dos Remedios</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Saripalli, Chandra" sort="Saripalli, Chandra" uniqKey="Saripalli C" first="Chandra" last="Saripalli">Chandra Saripalli</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Hidalgo, Carlos G" sort="Hidalgo, Carlos G" uniqKey="Hidalgo C" first="Carlos G." last="Hidalgo">Carlos G. Hidalgo</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Granzier, Henk L" sort="Granzier, Henk L" uniqKey="Granzier H" first="Henk L." last="Granzier">Henk L. Granzier</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Vonk Oordegraaf, Anton" sort="Vonk Oordegraaf, Anton" uniqKey="Vonk Oordegraaf A" first="Anton" last="Vonk-Noordegraaf">Anton Vonk-Noordegraaf</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></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><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="De Man, Frances S" sort="De Man, Frances S" uniqKey="De Man F" first="Frances S." last="De Man">Frances S. De Man</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease</title><idno type="eISSN">2047-9980</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca<sup>2+</sup> sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH.</p></sec><sec><title>Methods and Results</title><p>RV samples from PAH patients undergoing heart‐lung transplantation were compared to non‐failing donors (Don). <italic>Titin stiffness</italic> contribution to RV diastolic dysfunction was determined by Western‐blot analyses using antibodies to protein‐kinase‐A (PKA), Cα (PKCα) and Ca<sup>2+</sup>/calmoduling‐dependent‐kinase (CamKIIδ) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKCα sites were significantly less phosphorylated in PAH compared with donors (<italic>P</italic><0.0001). To test the functional relevance of PKA‐, PKCα‐, and CamK<sub>IIδ</sub>‐mediated titin phosphorylation, we measured the stiffness of single RV cardiomyocytes before and after kinase incubation. PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKCα further increased stiffness while CamK<sub>IIδ</sub> had no major effect. CamKIIδ activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca<sup>2+</sup> sensitivity is mediated by sarcomeric <italic>troponin I</italic> (cTnI) phosphorylation. We observed increased unphosphorylated cTnI in PAH compared with donors (<italic>P</italic><0.05) and reduced PKA‐mediated cTnI phosphorylation (Ser22/23) (<italic>P</italic><0.001). Finally, alterations in <italic>Ca</italic><sup><italic>2+</italic></sup><italic>‐handling proteins</italic> contribute to RV diastolic dysfunction due to insufficient diastolic Ca<sup>2+</sup> clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (<italic>P</italic><0.05).</p></sec><sec><title>Conclusions</title><p>Increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca<sup>2+</sup> handling proteins contribute to RV diastolic dysfunction in PAH.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rain, S" uniqKey="Rain S">S Rain</name></author><author><name sortKey="Handoko, Ml" uniqKey="Handoko M">ML Handoko</name></author><author><name sortKey="Trip, P" uniqKey="Trip P">P Trip</name></author><author><name sortKey="Gan, Ct" uniqKey="Gan C">CT‐J Gan</name></author><author><name sortKey="Westerhof, N" uniqKey="Westerhof N">N Westerhof</name></author><author><name sortKey="Stienen, Gj" uniqKey="Stienen G">GJ Stienen</name></author><author><name sortKey="Paulus, Wj" uniqKey="Paulus W">WJ Paulus</name></author><author><name sortKey="Ottenheijm, Cac" uniqKey="Ottenheijm C">CAC Ottenheijm</name></author><author><name sortKey="Marcus, Jt" uniqKey="Marcus J">JT Marcus</name></author><author><name sortKey="Dorfmuller, P" uniqKey="Dorfmuller P">P Dorfmüller</name></author><author><name sortKey="Guignabert, C" uniqKey="Guignabert C">C Guignabert</name></author><author><name sortKey="Humbert, M" uniqKey="Humbert M">M Humbert</name></author><author><name sortKey="Macdonald, P" uniqKey="Macdonald P">P Macdonald</name></author><author><name sortKey="Dos Remedios, C" uniqKey="Dos Remedios C">C Dos Remedios</name></author><author><name sortKey="Postmus, Pe" uniqKey="Postmus P">PE Postmus</name></author><author><name sortKey="Saripalli, C" uniqKey="Saripalli C">C Saripalli</name></author><author><name sortKey="Hidalgo, Cg" uniqKey="Hidalgo C">CG Hidalgo</name></author><author><name sortKey="Granzier, Hl" uniqKey="Granzier H">HL Granzier</name></author><author><name sortKey="Vonk Oordegraaf, A" uniqKey="Vonk Oordegraaf A">A Vonk‐Noordegraaf</name></author><author><name sortKey="Van Der Velden, J" uniqKey="Van Der Velden J">J van der Velden</name></author><author><name sortKey="De Man, Fs" uniqKey="De Man F">FS de Man</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Tombe, Pp" uniqKey="De Tombe P">PP De Tombe</name></author><author><name sortKey="Granzier, Hl" uniqKey="Granzier H">HL Granzier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fukuda, N" uniqKey="Fukuda N">N Fukuda</name></author><author><name sortKey="Granzier, Hl" uniqKey="Granzier H">HL Granzier</name></author><author><name sortKey="Ishiwata, S" uniqKey="Ishiwata S">S Ishiwata</name></author><author><name sortKey="Kurihara, S" uniqKey="Kurihara S">S Kurihara</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, S" uniqKey="Li S">S Li</name></author><author><name sortKey="Guo, W" uniqKey="Guo W">W Guo</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Am Heart Assoc</journal-id><journal-id journal-id-type="iso-abbrev">J Am Heart Assoc</journal-id><journal-id journal-id-type="hwp">ahaoa</journal-id><journal-id journal-id-type="publisher-id">jah3</journal-id><journal-title-group><journal-title>Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease</journal-title></journal-title-group><issn pub-type="epub">2047-9980</issn><publisher><publisher-name>Blackwell Publishing Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24895160</article-id><article-id pub-id-type="pmc">4309054</article-id><article-id pub-id-type="publisher-id">jah3558</article-id><article-id pub-id-type="doi">10.1161/JAHA.113.000716</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject><subj-group><subject>Heart Failure</subject></subj-group></subj-group></article-categories><title-group><article-title>Protein Changes Contributing to Right Ventricular Cardiomyocyte Diastolic Dysfunction in Pulmonary Arterial Hypertension</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rain</surname><given-names>Silvia</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au1"></xref><xref ref-type="aff" rid="au2"></xref></contrib><contrib contrib-type="author"><name><surname>Bos</surname><given-names>Denielli da Silva Goncalves</given-names></name><degrees>MSc</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>Handoko</surname><given-names>M. Louis</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au2"></xref><xref ref-type="aff" rid="au3"></xref></contrib><contrib contrib-type="author"><name><surname>Westerhof</surname><given-names>Nico</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au1"></xref><xref ref-type="aff" rid="au2"></xref></contrib><contrib contrib-type="author"><name><surname>Stienen</surname><given-names>Ger</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au2"></xref><xref ref-type="aff" rid="au4"></xref></contrib><contrib contrib-type="author"><name><surname>Ottenheijm</surname><given-names>Coen</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au2"></xref></contrib><contrib contrib-type="author"><name><surname>Goebel</surname><given-names>Max</given-names></name><degrees>Bsc</degrees><xref ref-type="aff" rid="au2"></xref></contrib><contrib contrib-type="author"><name><surname>Dorfmüller</surname><given-names>Peter</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au5"></xref><xref ref-type="aff" rid="au6"></xref></contrib><contrib contrib-type="author"><name><surname>Guignabert</surname><given-names>Christophe</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au5"></xref><xref ref-type="aff" rid="au6"></xref></contrib><contrib contrib-type="author"><name><surname>Humbert</surname><given-names>Marc</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au5"></xref><xref ref-type="aff" rid="au6"></xref><xref ref-type="aff" rid="au7"></xref><xref ref-type="aff" rid="au8"></xref></contrib><contrib contrib-type="author"><name><surname>Bogaard</surname><given-names>Harm‐Jan</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>dos Remedios</surname><given-names>Cris</given-names></name><degrees>DSc, PhD</degrees><xref ref-type="aff" rid="au9"></xref></contrib><contrib contrib-type="author"><name><surname>Saripalli</surname><given-names>Chandra</given-names></name><degrees>MSc</degrees><xref ref-type="aff" rid="au10"></xref></contrib><contrib contrib-type="author"><name><surname>Hidalgo</surname><given-names>Carlos G.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au10"></xref></contrib><contrib contrib-type="author"><name><surname>Granzier</surname><given-names>Henk L.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au10"></xref></contrib><contrib contrib-type="author"><name><surname>Vonk‐Noordegraaf</surname><given-names>Anton</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au1"></xref></contrib><contrib contrib-type="author"><name><surname>van der Velden</surname><given-names>Jolanda</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au2"></xref><xref ref-type="aff" rid="au11"></xref></contrib><contrib contrib-type="author"><name><surname>de Man</surname><given-names>Frances S.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au1"></xref><xref ref-type="aff" rid="au2"></xref></contrib><aff id="au1"><label>1</label><institution>Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research,</institution><addr-line>Amsterdam, The Netherlands (S.R., D.S.G.B., N.W., H.J.B., A.V.N., F.S.M.)</addr-line></aff><aff id="au2"><label>2</label><institution>Department of Physiology, VU University Medical Center/Institute for Cardiovascular Research,</institution><addr-line>Amsterdam, The Netherlands (S.R., L.H., N.W., G.S., C.O., M.G., J.V., F.S.M.)</addr-line></aff><aff id="au3"><label>3</label><institution>Department of Cardiology, VU University Medical Center/Institute for Cardiovascular Research,</institution><addr-line>Amsterdam, The Netherlands (L.H.)</addr-line></aff><aff id="au4"><label>4</label><institution>Department of Physics and Astronomy, VU University Medical Center/Institute for Cardiovascular Research,</institution><addr-line>Amsterdam, The Netherlands (G.S.)</addr-line></aff><aff id="au5"><label>5</label><institution>Faculté de Médecine, Université Paris‐Sud,</institution><addr-line>Le Kremlin‐Bicêtre, France (P.D., C.G., M.H.)</addr-line></aff><aff id="au6"><label>6</label><institution>Inserm U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue,</institution><addr-line>Le Plessis Robinson, France (P.D., C.G., M.H.)</addr-line></aff><aff id="au7"><label>7</label><institution>Service d'Anatomie Pathologique, Centre Chirurgical Marie Lannelongue,</institution><addr-line>Le Plessis Robinson, France (M.H.)</addr-line></aff><aff id="au8"><label>8</label><institution>Assistance Publique‐Hôspitaux de Paris, Service de Pneumologie, Département Hôspital Universitaire, Thorax innovation, (DHU‐TORINO),</institution><addr-line>Hôpital Bicêtre, France (M.H.)</addr-line></aff><aff id="au9"><label>9</label><institution>Muscle Research Unit, Discipline of Anatomy & Histology, Bosch Institute, The University of Sydney,</institution><addr-line>Sydney, Australia (C.R.)</addr-line></aff><aff id="au10"><label>10</label><institution>Sarver Molecular Cardiovascular Research Program, Department of Physiology, University of Arizona,</institution><addr-line>Tucson, AZ, The Netherlands (C.S., C.G.H., H.L.G.)</addr-line></aff><aff id="au11"><label>11</label><institution>ICIN – The Netherlands Heart Institute,</institution><addr-line>Amsterdam, The Netherlands (J.V.)</addr-line></aff></contrib-group><author-notes><corresp id="cor1"><bold>Correspondence to:</bold> Frances S. de Man, PhD, VU University Medical Center, Department of Pulmonology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E‐mail: <email>fs.deman@vumc.nl</email></corresp><fn><p>Dr van der Velden and Dr de Man contributed equally.</p></fn></author-notes><pub-date pub-type="collection"><month>6</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>3</day><month>6</month><year>2014</year></pub-date><volume>3</volume><issue>3</issue><elocation-id>e000716</elocation-id><history><date date-type="received"><day>05</day><month>3</month><year>2014</year></date><date date-type="accepted"><day>28</day><month>4</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
</copyright-statement><copyright-year>2014</copyright-year><license license-type="creative-commons"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">Creative Commons Attribution‐NonCommercial</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</license-p></license></permissions><abstract><sec><title>Background</title><p>Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca<sup>2+</sup> sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH.</p></sec><sec><title>Methods and Results</title><p>RV samples from PAH patients undergoing heart‐lung transplantation were compared to non‐failing donors (Don). <italic>Titin stiffness</italic> contribution to RV diastolic dysfunction was determined by Western‐blot analyses using antibodies to protein‐kinase‐A (PKA), Cα (PKCα) and Ca<sup>2+</sup>/calmoduling‐dependent‐kinase (CamKIIδ) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKCα sites were significantly less phosphorylated in PAH compared with donors (<italic>P</italic><0.0001). To test the functional relevance of PKA‐, PKCα‐, and CamK<sub>IIδ</sub>‐mediated titin phosphorylation, we measured the stiffness of single RV cardiomyocytes before and after kinase incubation. PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKCα further increased stiffness while CamK<sub>IIδ</sub> had no major effect. CamKIIδ activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca<sup>2+</sup> sensitivity is mediated by sarcomeric <italic>troponin I</italic> (cTnI) phosphorylation. We observed increased unphosphorylated cTnI in PAH compared with donors (<italic>P</italic><0.05) and reduced PKA‐mediated cTnI phosphorylation (Ser22/23) (<italic>P</italic><0.001). Finally, alterations in <italic>Ca</italic><sup><italic>2+</italic></sup><italic>‐handling proteins</italic> contribute to RV diastolic dysfunction due to insufficient diastolic Ca<sup>2+</sup> clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (<italic>P</italic><0.05).</p></sec><sec><title>Conclusions</title><p>Increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca<sup>2+</sup> handling proteins contribute to RV diastolic dysfunction in PAH.</p></sec></abstract><kwd-group><kwd>diastole</kwd><kwd>pulmonary heart disease</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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