Protein Changes Contributing to Right Ventricular Cardiomyocyte Diastolic Dysfunction in Pulmonary Arterial Hypertension
Identifieur interne : 003593 ( Main/Exploration ); précédent : 003592; suivant : 003594Protein 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.
Descripteurs français
- KwdFr :
- Adulte, Calcium-Calmodulin-Dependent Protein Kinase Type 2 (analyse), Calcium-Calmodulin-Dependent Protein Kinase Type 2 (physiologie), Connectine (analyse), Connectine (physiologie), Cyclic AMP-Dependent Protein Kinases (analyse), Cyclic AMP-Dependent Protein Kinases (physiologie), Dysfonction ventriculaire droite (physiopathologie), Femelle, Humains, Hypertension pulmonaire (physiopathologie), Myocytes cardiaques (), Myocytes cardiaques (physiologie), Mâle, Phosphorylation, Protein kinase C-alpha (analyse), Protein kinase C-alpha (physiologie), Technique de Western, Troponine I (physiologie), Ventricules cardiaques (), Ventricules cardiaques (physiopathologie), Études cas-témoins.
- MESH :
- analyse : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Connectine, Cyclic AMP-Dependent Protein Kinases, Protein kinase C-alpha.
- physiologie : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Connectine, Cyclic AMP-Dependent Protein Kinases, Myocytes cardiaques, Protein kinase C-alpha, Troponine I.
- physiopathologie : Dysfonction ventriculaire droite, Hypertension pulmonaire, Ventricules cardiaques.
- Adulte, Femelle, Humains, Myocytes cardiaques, Mâle, Phosphorylation, Technique de Western, Ventricules cardiaques, Études cas-témoins.
English descriptors
- KwdEn :
- Adult, Blotting, Western, Calcium-Calmodulin-Dependent Protein Kinase Type 2 (analysis), Calcium-Calmodulin-Dependent Protein Kinase Type 2 (physiology), Case-Control Studies, Connectin (analysis), Connectin (physiology), Cyclic AMP-Dependent Protein Kinases (analysis), Cyclic AMP-Dependent Protein Kinases (physiology), Female, Heart Ventricles (chemistry), Heart Ventricles (physiopathology), Humans, Hypertension, Pulmonary (physiopathology), Male, Myocytes, Cardiac (chemistry), Myocytes, Cardiac (physiology), Phosphorylation, Protein Kinase C-alpha (analysis), Protein Kinase C-alpha (physiology), Troponin I (physiology), Ventricular Dysfunction, Right (physiopathology).
- MESH :
- chemical , analysis : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Connectin, Cyclic AMP-Dependent Protein Kinases, Protein Kinase C-alpha.
- chemical , physiology : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Connectin, Cyclic AMP-Dependent Protein Kinases, Protein Kinase C-alpha, Troponin I.
- chemistry : Heart Ventricles, Myocytes, Cardiac.
- physiology : Myocytes, Cardiac.
- physiopathology : Heart Ventricles, Hypertension, Pulmonary, Ventricular Dysfunction, Right.
- Adult, Blotting, Western, Case-Control Studies, Female, Humans, Male, Phosphorylation.
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
Affiliations:
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Le document en format XML
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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><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Blotting, Western</term><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (analysis)</term><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (physiology)</term><term>Case-Control Studies</term><term>Connectin (analysis)</term><term>Connectin (physiology)</term><term>Cyclic AMP-Dependent Protein Kinases (analysis)</term><term>Cyclic AMP-Dependent Protein Kinases (physiology)</term><term>Female</term><term>Heart Ventricles (chemistry)</term><term>Heart Ventricles (physiopathology)</term><term>Humans</term><term>Hypertension, Pulmonary (physiopathology)</term><term>Male</term><term>Myocytes, Cardiac (chemistry)</term><term>Myocytes, Cardiac (physiology)</term><term>Phosphorylation</term><term>Protein Kinase C-alpha (analysis)</term><term>Protein Kinase C-alpha (physiology)</term><term>Troponin I (physiology)</term><term>Ventricular Dysfunction, Right (physiopathology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (analyse)</term><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (physiologie)</term><term>Connectine (analyse)</term><term>Connectine (physiologie)</term><term>Cyclic AMP-Dependent Protein Kinases (analyse)</term><term>Cyclic AMP-Dependent Protein Kinases (physiologie)</term><term>Dysfonction ventriculaire droite (physiopathologie)</term><term>Femelle</term><term>Humains</term><term>Hypertension pulmonaire (physiopathologie)</term><term>Myocytes cardiaques ()</term><term>Myocytes cardiaques (physiologie)</term><term>Mâle</term><term>Phosphorylation</term><term>Protein kinase C-alpha (analyse)</term><term>Protein kinase C-alpha (physiologie)</term><term>Technique de Western</term><term>Troponine I (physiologie)</term><term>Ventricules cardiaques ()</term><term>Ventricules cardiaques (physiopathologie)</term><term>Études cas-témoins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Connectin</term><term>Cyclic AMP-Dependent Protein Kinases</term><term>Protein Kinase C-alpha</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Connectin</term><term>Cyclic AMP-Dependent Protein Kinases</term><term>Protein Kinase C-alpha</term><term>Troponin I</term></keywords><keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Connectine</term><term>Cyclic AMP-Dependent Protein Kinases</term><term>Protein kinase C-alpha</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Heart Ventricles</term><term>Myocytes, Cardiac</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Connectine</term><term>Cyclic AMP-Dependent Protein Kinases</term><term>Myocytes cardiaques</term><term>Protein kinase C-alpha</term><term>Troponine I</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Myocytes, Cardiac</term></keywords><keywords scheme="MESH" qualifier="physiopathologie" xml:lang="fr"><term>Dysfonction ventriculaire droite</term><term>Hypertension pulmonaire</term><term>Ventricules cardiaques</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Heart Ventricles</term><term>Hypertension, Pulmonary</term><term>Ventricular Dysfunction, Right</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Blotting, Western</term><term>Case-Control Studies</term><term>Female</term><term>Humans</term><term>Male</term><term>Phosphorylation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Femelle</term><term>Humains</term><term>Myocytes cardiaques</term><term>Mâle</term><term>Phosphorylation</term><term>Technique de Western</term><term>Ventricules cardiaques</term><term>Études cas-témoins</term></keywords></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 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Vonk‐Noordegraaf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bogaard, Hj" uniqKey="Bogaard H">HJ Bogaard</name></author><author><name sortKey="Natarajan, R" uniqKey="Natarajan R">R Natarajan</name></author><author><name sortKey="Mizuno, S" uniqKey="Mizuno S">S Mizuno</name></author><author><name sortKey="Abbate, A" uniqKey="Abbate A">A Abbate</name></author><author><name sortKey="Chang, Pj" uniqKey="Chang P">PJ Chang</name></author><author><name sortKey="Chau, Vq" uniqKey="Chau V">VQ Chau</name></author><author><name sortKey="Hoke, Nn" uniqKey="Hoke N">NN Hoke</name></author><author><name sortKey="Kraskauskas, D" uniqKey="Kraskauskas D">D Kraskauskas</name></author><author><name sortKey="Kasper, M" uniqKey="Kasper M">M Kasper</name></author><author><name sortKey="Salloum, Fn" uniqKey="Salloum F">FN Salloum</name></author><author><name sortKey="Voelkel, Nf" uniqKey="Voelkel N">NF Voelkel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccain, Ml" uniqKey="Mccain M">ML McCain</name></author><author><name sortKey="Parker, Kk" uniqKey="Parker K">KK Parker</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Bogaard, Harm An" sort="Bogaard, Harm An" uniqKey="Bogaard H" first="Harm-Jan" last="Bogaard">Harm-Jan Bogaard</name><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><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><name sortKey="Dorfmuller, Peter" sort="Dorfmuller, Peter" uniqKey="Dorfmuller P" first="Peter" last="Dorfmüller">Peter Dorfmüller</name><name sortKey="Dos Remedios, Cris" sort="Dos Remedios, Cris" uniqKey="Dos Remedios C" first="Cris" last="Dos Remedios">Cris Dos Remedios</name><name sortKey="Goebel, Max" sort="Goebel, Max" uniqKey="Goebel M" first="Max" last="Goebel">Max Goebel</name><name sortKey="Granzier, Henk L" sort="Granzier, Henk L" uniqKey="Granzier H" first="Henk L." last="Granzier">Henk L. Granzier</name><name sortKey="Guignabert, Christophe" sort="Guignabert, Christophe" uniqKey="Guignabert C" first="Christophe" last="Guignabert">Christophe Guignabert</name><name sortKey="Handoko, M Louis" sort="Handoko, M Louis" uniqKey="Handoko M" first="M. Louis" last="Handoko">M. Louis Handoko</name><name sortKey="Hidalgo, Carlos G" sort="Hidalgo, Carlos G" uniqKey="Hidalgo C" first="Carlos G." last="Hidalgo">Carlos G. Hidalgo</name><name sortKey="Humbert, Marc" sort="Humbert, Marc" uniqKey="Humbert M" first="Marc" last="Humbert">Marc Humbert</name><name sortKey="Ottenheijm, Coen" sort="Ottenheijm, Coen" uniqKey="Ottenheijm C" first="Coen" last="Ottenheijm">Coen Ottenheijm</name><name sortKey="Rain, Silvia" sort="Rain, Silvia" uniqKey="Rain S" first="Silvia" last="Rain">Silvia Rain</name><name sortKey="Saripalli, Chandra" sort="Saripalli, Chandra" uniqKey="Saripalli C" first="Chandra" last="Saripalli">Chandra Saripalli</name><name sortKey="Stienen, Ger" sort="Stienen, Ger" uniqKey="Stienen G" first="Ger" last="Stienen">Ger Stienen</name><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><name sortKey="Vonk Oordegraaf, Anton" sort="Vonk Oordegraaf, Anton" uniqKey="Vonk Oordegraaf A" first="Anton" last="Vonk-Noordegraaf">Anton Vonk-Noordegraaf</name><name sortKey="Westerhof, Nico" sort="Westerhof, Nico" uniqKey="Westerhof N" first="Nico" last="Westerhof">Nico Westerhof</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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