ArticleJournal of the American Heart Association2014
Protein changes contributing to right ventricular cardiomyocyte diastolic dysfunction in pulmonary arterial hypertension.
Article in Journal of the American Heart Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 78 citations in OpenAlex.
- Right Heart Diastology, Where Are We Now?Circulation research · 2026Review
- TAPSE/PASP combined with IVC can identify poor prognosis in PAH patients with low and intermediate risk.Clinical rheumatology · 2026Article
- PDE9A Promotes Calcium-Handling Dysfunction in Right Heart Failure via cGMP-PKG Pathway Suppression: A Mechanistic and Therapeutic Review.International journal of molecular sciences · 2025Review
- Pulmonary Arterial Hypertension Induces Compensatory Increase of Left Ventricular Contractility Indexes in Rats in Response to Its Filling Insufficiency.Bulletin of experimental biology and medicine · 2025Article
- The selective serotonin reuptake inhibitor paroxetine improves right ventricular systolic function in experimental pulmonary hypertension.Journal of molecular and cellular cardiology plus · 2024Article
- Connexin43, A Promising Target to Reduce Cardiac Arrhythmia Burden in Pulmonary Arterial Hypertension.International journal of molecular sciences · 2024Review
- Untangling the mechanisms of pulmonary arterial hypertension-induced right ventricular stiffening in a large animal model.Acta biomaterialia · 2023Article
- Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension.Circulation. Heart failure · 2023Article
- Mesenchymal stem cell-derived extracellular vesicles prevent the formation of pulmonary arterial hypertension through a microRNA-200b-dependent mechanism.Respiratory research · 2023Article
- Untangling the mechanisms of pulmonary hypertension-induced right ventricular stiffening in a large animal model.bioRxiv : the preprint server for biology · 2023Article
- Beneficial Effects of Low-Intensity Pulsed Ultrasound Therapy on Right Ventricular Dysfunction in Animal Models.JACC. Basic to translational science · 2023Article
- Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension.International journal of molecular sciences · 2023Review
- Titin (TTN): from molecule to modifications, mechanics, and medical significance.Cardiovascular research · 2022Review
- Right atrial function is associated with right venticular diastolic stiffness: RA-RV interaction in pulmonary arterial hypertension.The European respiratory journal · 2022Article
- Article
- The thromboxane receptor antagonistFrontiers in cardiovascular medicine · 2022Article
- Proteomic and Metabolomic Analyses of Right Ventricular Failure due to Pulmonary Arterial Hypertension.Frontiers in molecular biosciences · 2022Article
- Article
- The Sarcomeric Spring Protein Titin: Biophysical Properties, Molecular Mechanisms, and Genetic Mutations Associated with Heart Failure and Cardiomyopathy.Current cardiology reports · 2021Review
- Interventricular Differences of Signaling Pathways-Mediated Regulation of Cardiomyocyte Function in Response to High Oxidative Stress in the Post-Ischemic Failing Rat Heart.Antioxidants (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundRight ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca(2+) sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH. METHODS AND
resultsRV samples from PAH patients undergoing heart-lung transplantation were compared to non-failing donors (Don). Titin stiffness contribution to RV diastolic dysfunction was determined by Western-blot analyses using antibodies to protein-kinase-A (PKA), Cα (PKCα) and Ca(2+)/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 (P<0.0001). To test the functional relevance of PKA-, PKCα-, and CamKIIδ-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 CamKIIδ had no major effect. CamKIIδ activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca(2+) sensitivity is mediated by sarcomeric troponin I (cTnI) phosphorylation. We observed increased unphosphorylated cTnI in PAH compared with donors (P<0.05) and reduced PKA-mediated cTnI phosphorylation (Ser22/23) (P<0.001). Finally, alterations in Ca(2+)-handling proteins contribute to RV diastolic dysfunction due to insufficient diastolic Ca(2+) clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (P<0.05).
conclusionsIncreased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca(2+) handling proteins contribute to RV diastolic dysfunction in PAH.
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