ArticleCirculation. Cardiovascular genetics2014
Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins.
Article in Circulation. Cardiovascular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 67 citations in OpenAlex.
- Experimental Models of Hypertrophic Cardiomyopathy: A Systematic Review.JACC. Basic to translational science · 2025Review
- Reduction in myofilament CaFrontiers in physiology · 2025Article
- Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies.Biomedicines · 2024Review
- Exploring contractile protein mechanisms and target medications for cardiomyopathic patients with diastolic dysfunction.Pediatric discovery · 2024Review
- Troponin I Tyrosine Phosphorylation Beneficially Accelerates Diastolic Function.Circulation research · 2024Article
- Three-dimensional spatial quantitative analysis of cardiac lymphatics in the mouse heart.Microcirculation (New York, N.Y. : 1994) · 2023Article
- A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- A green tea extract catechin EGCg: Therapeutic potential for pediatric cardiomyopathies.Pediatric discovery · 2023Review
- The lack of Troponin I Ser-23/24 phosphorylation is detrimental to in vivo cardiac function and exacerbates cardiac disease.Journal of molecular and cellular cardiology · 2023Article
- Altered coronary artery function, arteriogenesis and endothelial YAP signaling in postnatal hypertrophic cardiomyopathy.Frontiers in physiology · 2023Article
- The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy.International journal of drug discovery and pharmacology · 2022Article
- Truncation of the N-terminus of cardiac troponin I initiates adaptive remodeling of the myocardial proteosome via phosphorylation of mechano-sensitive signaling pathways.Molecular and cellular biochemistry · 2022Article
- Suppression of lusitropy as a disease mechanism in cardiomyopathies.Frontiers in cardiovascular medicine · 2022Review
- Ventricular arrhythmia and sudden cardiac death in hypertrophic cardiomyopathy: From bench to bedside.Frontiers in cardiovascular medicine · 2022Review
- Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach.Life (Basel, Switzerland) · 2021Article
- Pushing the Limits of Medical Management in HCM: A Review of Current Pharmacological Therapy Options.International journal of molecular sciences · 2021Review
- NHJournal of cellular signaling · 2021Article
- Strategies for targeting the cardiac sarcomere: avenues for novel drug discovery.Expert opinion on drug discovery · 2020Review
- Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response.Frontiers in physiology · 2020Article
- Hypertrophic Cardiomyopathy: A Vicious Cycle Triggered by Sarcomere Mutations and Secondary Disease Hits.Antioxidants & redox signaling · 2019Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundHypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca(2+) sensitivity, and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype. METHODS AND
resultsWe used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca(2+) sensitivity, severe hypertrophy, and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca(2+) sensitivity in Tm180 mice by generating a double transgenic mouse line. We crossed Tm180 mice with mice expressing a pseudophosphorylated cardiac troponin I (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca(2+) sensitivity compared with wild-type mice. The development of pathological hypertrophy did not occur in mice expressing both Tm180 and TnI-PP. Left ventricle performance was improved in double transgenic compared with their Tm180 littermates, which express wild-type cardiac troponin I. Hearts of double transgenic mice demonstrated no changes in expression of phospholamban and sarcoplasmic reticulum Ca(2+) ATPase, increased levels of phospholamban and troponin T phosphorylation, and reduced phosphorylation of TnI compared with Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of extracellular signal-regulated kinase and zinc finger-containing transcription factor GATA in Tm180 hearts.
conclusionsOur data strongly indicate that reduction of myofilament sensitivity to Ca(2+) and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.
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