Epigallocatechin-3-Gallate Accelerates Relaxation and Ca2+ Transient Decay and Desensitizes Myofilaments in Healthy and Mybpc3-Targeted Knock-in Cardiomyopathic Mice

Friedrich, Felix W.; Flenner, Frederik; Nasib, Mahtab; Eschenhagen, Thomas; Carrier, Lucie

doi:10.3389/fphys.2016.00607

Cited by 17 publications

(32 citation statements)

References 60 publications

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“…The next day strips were either used directly for measurements or stored at −20°C in a 50% glycerol/relaxing solution with protease inhibitors (EDTA‐free, complete tablets, mini, Roche). Measurement of contractile function was performed using a fiber test system (1400A; Aurora Scientific) as reported previously (Friedrich et al , ; Stucker et al , ). A Hill equation was fitted to the data points (Hill et al , ) to estimate pCa 50 as the free Ca 2+ concentration yielding 50% of the maximal force and nH representing the Hill coefficient.…”

Section: Methodsmentioning

confidence: 99%

Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

et al. 2019

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Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α‐actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient‐derived human‐induced pluripotent stem cells (hiPSCs) and show that hiPSC‐derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca2+ sensitivity, and also prolonged action potential duration and enhanced L‐type Ca2+ current. The L‐type Ca2+ channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM‐affected son and sister of the index patient. These data provide evidence for this ACTN2 mutation to be disease‐causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof‐of‐principle for the use of hiPSC for personalized treatment of cardiomyopathies.

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Section: Methodsmentioning

confidence: 99%

Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

et al. 2019

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“…Mechanistic studies have demonstrated that tea polyphenols may influence many aspects of cardiovascular function by their interaction with a list of intracellular target sites, such as several ion channels and ion exchangers (Na ), intracellular Ca 2+ storage, and sarcomeric Troponin protein [7,13,15]. Another study reported that EGCG acute administration in cardiomyocytes, isolated from a transgenic mice model of hypertrophic cardiomyopathy, ameliorated sarcomere shortening and lowered relaxation time by decreasing the thin myofilament Ca 2+ sensitivity [10]. More recent data also suggest an epigenetic regulation of gene expression induced by these compounds, such as inhibition of DNA methyltransferase resulting in re-activation of methylation-silenced genes, and inhibition of class I histone-deacetylases (HDAC1, HDAC2 and HDAC3) [13].…”

Section: Introductionmentioning

confidence: 99%

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

Bocchi

Savi

Naponelli

et al. 2018

Cell Physiol Biochem

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Background/Aims: Dietary polyphenols from green tea have been shown to possess cardio-protective activities in different experimental models of heart diseases and age-related ventricular dysfunction. The present study was aimed at evaluating whether long term in vivo administration of green tea extracts (GTE), can exert positive effects on the normal heart, with focus on the underlying mechanisms. Methods: The study population consisted of 20 male adult Wistar rats. Ten animals were given 40 mL/day tap water solution of GTE (concentration 0.3%) for 4 weeks (GTE group). The same volume of water was administered to the 10 remaining control rats (CTRL). Then, in vivo and ex vivo measurements of cardiac function were performed in the same animal, at the organ (hemodynamics) and cellular (cardiomyocyte mechanical properties and intracellular calcium dynamics) levels. On cardiomyocytes and myocardial tissue samples collected from the same in vivo studied animals, we evaluated: (1) the intracellular content of ATP, (2) the endogenous mitochondrial respiration, (3) the expression levels of the Sarcoplasmic Reticulum Ca²⁺-dependent ATPase 2a (SERCA2), the Phospholamban (PLB) and the phosphorylated form of PLB, the L-type Ca²⁺ channel, the Na⁺-Ca²⁺ exchanger, and the ryanodine receptor 2. Results: GTE cardiomyocytes exhibited a hyperdynamic contractility compared with CTRL (the rate of shortening and re-lengthening, the fraction of shortening, the amplitude of calcium transient, and the rate of cytosolic calcium removal were significantly increased). A faster isovolumic relaxation was also observed at the organ level. Consistent with functional data, we measured a significant increase in the intracellular ATP content supported by enhanced endogenous mitochondrial respiration in GTE cardiomyocytes, as well as higher values of the ratios phosphorylated-PLB/PLB and SERCA2/PLB. Conclusions: Long-term in vivo administration of GTE improves cell mechanical properties and intracellular calcium dynamics in normal cardiomyocytes, by increasing energy availability and removing the inhibitory effect of PLB on SERCA2.

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“…; Friedrich et al . ), a condition in which small changes in cytosolic Ca 2+ can evoke strong changes in contractility. Diltiazem itself neither influenced myofilament Ca 2+ sensitivity directly nor indirectly via changing phosphorylation of PKA targets (data not shown).…”

Section: Introductionmentioning

confidence: 99%

Diltiazem prevents stress‐induced contractile deficits in cardiomyocytes, but does not reverse the cardiomyopathy phenotype in Mybpc3‐knock‐in mice

Flenner

Geertz

Reischmann-Düsener

et al. 2017

The Journal of Physiology

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Left ventricular hypertrophy, diastolic dysfunction and fibrosis are the main features of hypertrophic cardiomyopathy (HCM). Guidelines recommend β-adrenoceptor or Ca channel antagonists as pharmacological treatment. The Ca channel blocker diltiazem recently showed promising beneficial effects in pre-clinical HCM, particularly in patients carrying MYBPC3 mutations. In the present study we evaluated whether diltiazem could ameliorate or reverse the disease phenotype in cells and in vivo in an Mybpc3-targeted knock-in (KI) mouse model of HCM. Sarcomere shortening and Ca transients were measured in KI and wild-type (WT) cardiomyocytes in basal conditions (1-Hz pacing) and under stress conditions (30 nm isoprenaline, 5-Hz pacing) with or without pre-treatment with 1 μm diltiazem. KI cardiomyocytes exhibited lower diastolic sarcomere length (dSL) at baseline, a tendency to a stronger positive inotropic response to isoprenaline than WT, a marked reduction of dSL and a tendency towards arrhythmias under stress conditions. Pre-treatment of cardiomyocytes with 1 μm diltiazem reduced the drop in dSL and arrhythmia frequency in KI, and attenuated the positive inotropic effect of isoprenaline. Furthermore, diltiazem reduced the contraction amplitude at 5 Hz but did not affect diastolic Ca load and Ca transient amplitude. Six months of diltiazem treatment of KI mice did not reverse cardiac hypertrophy and dysfunction, activation of the fetal gene program or fibrosis. In conclusion, diltiazem blunted the response to isoprenaline in WT and KI cardiomyocytes and improved diastolic relaxation under stress conditions in KI cardiomyocytes. This beneficial effect of diltiazem in cells did not translate in therapeutic efficacy when applied chronically in KI mice.

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Epigallocatechin-3-Gallate Accelerates Relaxation and Ca2+ Transient Decay and Desensitizes Myofilaments in Healthy and Mybpc3-Targeted Knock-in Cardiomyopathic Mice

Cited by 17 publications

References 60 publications

Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

Disease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

Diltiazem prevents stress‐induced contractile deficits in cardiomyocytes, but does not reverse the cardiomyopathy phenotype in Mybpc3‐knock‐in mice

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