ArticleProceedings of the National Academy of Sciences of the United States of America2015
ADP-stimulated contraction: A predictor of thin-filament activation in cardiac disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 45 citations in OpenAlex.
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- Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy.EMBO molecular medicine · 2025Article
- The Heart Has Intrinsic Ketogenic Capacity that Mediates NADCirculation research · 2025Article
- Left ventricular rigor mortis interferes with postmortem aortic root geometry.International journal of legal medicine · 2025Article
- Proteomic and metabolomic analyses of the human adult myocardium reveal ventricle-specific regulation in end-stage cardiomyopathies.Communications biology · 2024Article
- Definitional Challenges in Understanding Hypertrophic Cardiomyopathy.Diagnostics (Basel, Switzerland) · 2024Review
- The Efficacy of Risk Factor Modification Compared to NADJACC. Basic to translational science · 2024Article
- Myosin-binding protein H-like regulates myosin-binding protein distribution and function in atrial cardiomyocytes.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Increased Chamber Resting Tone Is a Key Determinant of Left Ventricular Diastolic Dysfunction.Circulation. Heart failure · 2023Article
- Mavacamten, a precision medicine for hypertrophic cardiomyopathy: From a motor protein to patients.Science advances · 2023Review
- Mechano-energetic uncoupling in hypertrophic cardiomyopathy: Pathophysiological mechanisms and therapeutic opportunities.Journal of molecular and cellular cardiology plus · 2023Review
- Review
- A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue.Journal of molecular and cellular cardiology plus · 2022Article
- Low expression of the K280NJournal of molecular and cellular cardiology plus · 2022Article
- Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach.Life (Basel, Switzerland) · 2021Article
- Mechanisms underlying the pathophysiology of heart failure with preserved ejection fraction: the tip of the iceberg.Heart failure reviews · 2021Review
- Genetic Restrictive Cardiomyopathy: Causes and Consequences-An Integrative Approach.International journal of molecular sciences · 2021Review
- Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.Circulation. Heart failure · 2021Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Diastolic dysfunction is general to all idiopathic dilated (IDCM) and hypertrophic cardiomyopathy (HCM) patients. Relaxation deficits may result from increased actin-myosin formation during diastole due to altered tropomyosin position, which blocks myosin binding to actin in the absence of Ca(2+). We investigated whether ADP-stimulated force development (without Ca(2+)) can be used to reveal changes in actin-myosin blockade in human cardiomyopathy cardiomyocytes. Cardiac samples from HCM patients, harboring thick-filament (MYH7mut, MYBPC3mut) and thin-filament (TNNT2mut, TNNI3mut) mutations, and IDCM were compared with sarcomere mutation-negative HCM (HCMsmn) and nonfailing donors. Myofilament ADP sensitivity was higher in IDCM and HCM compared with donors, whereas it was lower for MYBPC3. Increased ADP sensitivity in IDCM, HCMsmn, and MYH7mut was caused by low phosphorylation of myofilament proteins, as it was normalized to donors by protein kinase A (PKA) treatment. Troponin exchange experiments in a TNNT2mut sample corrected the abnormal actin-myosin blockade. In MYBPC3trunc samples, ADP sensitivity highly correlated with cardiac myosin-binding protein-C (cMyBP-C) protein level. Incubation of cardiomyocytes with cMyBP-C antibody against the actin-binding N-terminal region reduced ADP sensitivity, indicative of cMyBP-C's role in actin-myosin regulation. In the presence of Ca(2+), ADP increased myofilament force development and sarcomere stiffness. Enhanced sarcomere stiffness in sarcomere mutation-positive HCM samples was irrespective of the phosphorylation background. In conclusion, ADP-stimulated contraction can be used as a tool to study how protein phosphorylation and mutant proteins alter accessibility of myosin binding on actin. In the presence of Ca(2+), pathologic [ADP] and low PKA-phosphorylation, high actin-myosin formation could contribute to the impaired myocardial relaxation observed in cardiomyopathies.
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