Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy

Schlossarek, Saskia; Singh, Simran Jeet; Geertz, Birgit; Schulz, Herbert; Reischmann, Silke; Hübner, Norbert; Carrier, Lucie

doi:10.3389/fphys.2014.00484

Cited by 26 publications

(18 citation statements)

References 28 publications

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“…The Mybpc3 KI cardiomyopathy mouse model was generated by the targeted insertion of a G > A transition on the last nucleotide of exon 6 and maintained on the Black Swiss background (Vignier et al, 2009; Fraysse et al, 2012; Schlossarek et al, 2012, 2014; Gedicke-Hornung et al, 2013; Mearini et al, 2013, 2014; Stöhr et al, 2013; Friedrich et al, 2014; Najafi et al, 2015; Thottakara et al, 2015; Flenner et al, 2016). This study was carried out in accordance with the recommendations of the guide for the care and use of laboratory animals published by the NIH (Publication No.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disease with left ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction. Increased myofilament Ca2+ sensitivity could be the underlying cause of diastolic dysfunction. Epigallocatechin-3-gallate (EGCg), a catechin found in green tea, has been reported to decrease myofilament Ca2+ sensitivity in HCM models with troponin mutations. However, whether this is also the case for HCM-associated thick filament mutations is not known. Therefore, we evaluated whether EGCg affects the behavior of cardiomyocytes and myofilaments of an HCM mouse model carrying a gene mutation in cardiac myosin-binding protein C and exhibiting both increased myofilament Ca2+ sensitivity and diastolic dysfunction.Methods and Results: Acute effects of EGCg were tested on fractional sarcomere shortening and Ca2+ transients in intact ventricular myocytes and on force-Ca2+ relationship of skinned ventricular muscle strips isolated from Mybpc3-targeted knock-in (KI) and wild-type (WT) mice. Fractional sarcomere shortening and Ca2+ transients were analyzed at 37°C under 1-Hz pacing in the absence or presence of EGCg (1.8 μM). At baseline and in the absence of Fura-2, KI cardiomyocytes displayed lower diastolic sarcomere length, higher fractional sarcomere shortening, longer time to peak shortening and time to 50% relengthening than WT cardiomyocytes. In WT and KI neither diastolic sarcomere length nor fractional sarcomere shortening were influenced by EGCg treatment, but relaxation time was reduced, to a greater extent in KI cells. EGCg shortened time to peak Ca2+ and Ca2+ transient decay in Fura-2-loaded WT and KI cardiomyocytes. EGCg did not influence phosphorylation of phospholamban. In skinned cardiac muscle strips, EGCg (30 μM) decreased Ca2+ sensitivity in both groups.Conclusion: EGCg hastened relaxation and Ca2+ transient decay to a larger extent in KI than in WT cardiomyocytes. This effect could be partially explained by myofilament Ca2+ desensitization.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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“…The Mybpc3 KI cardiomyopathy mouse model was generated by the targeted insertion of a G>A transition on the last nucleotide of exon 6 (Vignier et al, 2009 ; Fraysse et al, 2012 ; Schlossarek et al, 2012 , 2014 ; Gedicke-Hornung et al, 2013 ; Mearini et al, 2013 , 2014 ; Stohr et al, 2013 ; Friedrich et al, 2014 ; Najafi et al, 2015 ; Thottakara et al, 2015 ; Flenner et al, 2016 , 2017 ). Mice were maintained on the C57 background.…”

Section: Methodsmentioning

confidence: 99%

Nebivolol Desensitizes Myofilaments of a Hypertrophic Cardiomyopathy Mouse Model

et al. 2017

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Background: Hypertrophic cardiomyopathy (HCM) patients often present with diastolic dysfunction and a normal to supranormal systolic function. To counteract this hypercontractility, guideline therapies advocate treatment with beta-adrenoceptor and Ca2+ channel blockers. One well established pathomechanism for the hypercontractile phenotype frequently observed in HCM patients and several HCM mouse models is an increased myofilament Ca2+ sensitivity. Nebivolol, a commonly used beta-adrenoceptor antagonist, has been reported to lower maximal force development and myofilament Ca2+ sensitivity in rabbit and human heart tissues. The aim of this study was to evaluate the effect of nebivolol in cardiac muscle strips of an established HCM Mybpc3 mouse model. Furthermore, we investigated actions of nebivolol and epigallocatechin-gallate, which has been shown to desensitize myofilaments for Ca2+ in mouse and human HCM models, in cardiac strips of HCM patients with a mutation in the most frequently mutated HCM gene MYBPC3.Methods and Results: Nebivolol effects were tested on contractile parameters and force-Ca2+ relationship of skinned ventricular muscle strips isolated from Mybpc3-targeted knock-in (KI), wild-type (WT) mice and cardiac strips of three HCM patients with MYBPC3 mutations. At baseline, KI strips showed no difference in maximal force development compared to WT mouse heart strips. Neither 1 nor 10 μM nebivolol had an effect on maximal force development in both genotypes. 10 μM nebivolol induced myofilament Ca2+ desensitization in WT strips and to a greater extent in KI strips. Neither 1 nor 10 μM nebivolol had an effect on Ca2+ sensitivity in cardiac muscle strips of three HCM patients with MYBPC3 mutations, whereas epigallocatechin-gallate induced a right shift in the force-Ca2+ curve.Conclusion: Nebivolol induced a myofilament Ca2+ desensitization in both WT and KI strips, which was more pronounced in KI muscle strips. In human cardiac muscle strips of three HCM patients nebivolol had no effect on myofilament Ca2+ sensitivity.

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“…Of note, the decreased proteasome activity reported in HCM and failing human hearts (Predmore et al, 2010 ) supports the hypothesis of misfolded p53 accumulation and the formation of higher-order oligomers of this tumor suppressor. Furthermore, transgenic mice expressing a myosin-binding protein C mutation that were treated with a proteasome inhibitor were not able to regress the HCM phenotype but rather slightly improved cardiac function (Schlossarek et al, 2014 ). The loss-of-function and gain-of-function phenotypes of oligomeric and aggregated p53 and their involvement in the development of HCM are still matters of speculation and require further exploration.…”

Section: Signaling In Hypertrophic Cardiomyopathymentioning

confidence: 99%

Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

Marques

Oliveira

2016

Front. Physiol.

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Inherited myopathies affect both skeletal and cardiac muscle and are commonly associated with genetic dysfunctions, leading to the production of anomalous proteins. In cardiomyopathies, mutations frequently occur in sarcomeric genes, but the cause-effect scenario between genetic alterations and pathological processes remains elusive. Hypertrophic cardiomyopathy (HCM) was the first cardiac disease associated with a genetic background. Since the discovery of the first mutation in the β-myosin heavy chain, more than 1400 new mutations in 11 sarcomeric genes have been reported, awarding HCM the title of the “disease of the sarcomere.” The most common macroscopic phenotypes are left ventricle and interventricular septal thickening, but because the clinical profile of this disease is quite heterogeneous, these phenotypes are not suitable for an accurate diagnosis. The development of genomic approaches for clinical investigation allows for diagnostic progress and understanding at the molecular level. Meanwhile, the lack of accurate in vivo models to better comprehend the cellular events triggered by this pathology has become a challenge. Notwithstanding, the imbalance of Ca2+ concentrations, altered signaling pathways, induction of apoptotic factors, and heart remodeling leading to abnormal anatomy have already been reported. Of note, a misbalance of signaling biomolecules, such as kinases and tumor suppressors (e.g., Akt and p53), seems to participate in apoptotic and fibrotic events. In HCM, structural and cellular information about defective sarcomeric proteins and their altered interactome is emerging but still represents a bottleneck for developing new concepts in basic research and for future therapeutic interventions. This review focuses on the structural and cellular alterations triggered by HCM-causing mutations in troponin and tropomyosin proteins and how structural biology can aid in the discovery of new platforms for therapeutics. We highlight the importance of a better understanding of allosteric communications within these thin-filament proteins to decipher the HCM pathological state.

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Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy

Cited by 26 publications

References 28 publications

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

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

Nebivolol Desensitizes Myofilaments of a Hypertrophic Cardiomyopathy Mouse Model

Cardiac Troponin and Tropomyosin: Structural and Cellular Perspectives to Unveil the Hypertrophic Cardiomyopathy Phenotype

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