ArticleBritish journal of pharmacology2012
JTV519 (K201) reduces sarcoplasmic reticulum Ca²⁺ leak and improves diastolic function in vitro in murine and human non-failing myocardium.
Article in British journal of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 53 citations in OpenAlex.
- Simultaneous optical recording of action potentials and calcium transients in cardiac single cells differentiated from type 1 CPVT-iPS cells.Frontiers in physiology · 2025Article
- HDAC Inhibition Regulates Cardiac Function by Increasing Myofilament Calcium Sensitivity and Decreasing Diastolic Tension.Pharmaceutics · 2022Article
- Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases.International journal of molecular sciences · 2022Review
- Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure.Expert opinion on therapeutic targets · 2020Review
- Electrophysiological and Contractile Effects of Disopyramide in Patients With Obstructive Hypertrophic Cardiomyopathy: A Translational Study.JACC. Basic to translational science · 2019Article
- Small-conductance calcium-activated potassium current modulates the ventricular escape rhythm in normal rabbit hearts.Heart rhythm · 2019Article
- Toll-like receptor 4-induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum CaThe Journal of biological chemistry · 2018Article
- New Insights in Cardiac Calcium Handling and Excitation-Contraction Coupling.Advances in experimental medicine and biology · 2018Review
- Calcium-Mediated Oscillation in Membrane Potentials and Atrial-Triggered Activity in Atrial Cells of Casq2Frontiers in physiology · 2018Article
- Heart failure with preserved ejection fraction: current management and future strategies : Expert opinion on the behalf of the Nucleus of the "Heart Failure Working Group" of the German Society of Cardiology (DKG).Clinical research in cardiology : official journal of the German Cardiac Society · 2018Review
- An optogenetic arrhythmia model to study catecholaminergic polymorphic ventricular tachycardia mutations.Scientific reports · 2017Article
- Heart Failure with Preserved Ejection Fraction and Future Pharmacological Strategies: a Glance in the Crystal Ball.Current cardiology reports · 2017Review
- A two dimensional electromechanical model of a cardiomyocyte to assess intra-cellular regional mechanical heterogeneities.PloS one · 2017Article
- Conformation of ryanodine receptor-2 gates store-operated calcium entry in rat pulmonary arterial myocytes.Cardiovascular research · 2016Article
- Review
- Chasing cardiac physiology and pathology down the CaMKII cascade.American journal of physiology. Heart and circulatory physiology · 2015Review
- Article
- TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.Cardiovascular research · 2015Article
- Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes: impact on swelling-induced negative inotropic effect.Cardiovascular research · 2014Article
- Novel drug targets in clinical development for heart failure.European journal of clinical pharmacology · 2014Review
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeCa²⁺ leak from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2s) contributes to cardiomyocyte dysfunction. RyR2 Ca²⁺ leak has been related to RyR2 phosphorylation. In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca²⁺ leak. We investigated whether JTV519 stabilizes RyR2s without increasing RyR2 phosphorylation in mice and in non-failing human myocardium and explored underlying mechanisms. EXPERIMENTAL APPROACH: SR Ca²⁺ leak was induced by ouabain in murine cardiomyocytes. [Ca²⁺]-transients, SR Ca²⁺ load and RyR2-mediated Ca²⁺ leak (sparks/waves) were quantified, with or without JTV519 (1 µmol·L⁻¹). Contribution of Ca²⁺ -/calmodulin-dependent kinase II (CaMKII) was assessed by KN-93 and Western blot (RyR2-Ser(2814) phosphorylation). Effects of JTV519 on contractile force were investigated in non-failing human ventricular trabeculae. KEY
resultsOuabain increased systolic and diastolic cytosolic [Ca²⁺](i) , SR [Ca²⁺], and SR Ca²⁺ leak (Ca²⁺ spark (SparkF) and Ca²⁺ wave frequency), independently of CaMKII and RyR-Ser(2814) phosphorylation. JTV519 decreased SparkF but also SR Ca²⁺ load. At matched SR [Ca²⁺], Ca²⁺ leak was significantly reduced by JTV519, but it had no effect on fractional Ca²⁺ release or Ca²⁺ wave propagation velocity. In human muscle, JTV519 was negatively inotropic at baseline but significantly enhanced ouabain-induced force and reduced its deleterious effects on diastolic function. CONCLUSIONS AND IMPLICATIONS: JTV519 was effective in reducing SR Ca²⁺ leak by specifically regulating RyR2 opening at diastolic [Ca²⁺](i) in the absence of increased RyR2 phosphorylation at Ser(2814) , extending the potential use of JTV519 to conditions of acute cellular Ca²⁺ overload.
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