Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

Yampolsky, Pessah; Koenen, Michael; Mosqueira, Matías; Geschwill, Pascal; Nauck, Sebastian; Witzenberger, Monika; Seyler, Claudia; Fink, Thomas; Kruska, Mathieu; Bruehl, Claus; Schwoerer, Alexander Peter; Ehmke, Heimo; Fink, Rainer H. A.; Draguhn, Andreas; Thomas, Dierk; Katus, Hugo A.; Schweizer, Patrick

doi:10.1038/s41467-019-11261-2

Cited by 27 publications

(26 citation statements)

References 57 publications

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“…Increased HCN4 expression was reported in failing hearts in previous studies, which was consistent with our results. HCN4 overexpression mediated I f augmentation in cardiomyocytes and led to cardiac remodeling (Yampolsky et al, 2019). Although functions of NONRATT013999 and NONRATT027756 were still unclear, the expression levels of these lncRNAs were increased in HF.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Chen

Xue

et al. 2019

Front. Genet.

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Aim: Heart failure (HF) is the end stage of various cardiovascular diseases. However, the precise regulation of gene expression profiles and functional mechanisms of long non-coding RNAs (lncRNAs) in HF remain to be elucidated. The present study aimed to identify the differentially expressed profiles and interaction of messenger RNAs (mRNAs) and lncRNAs in pressure overload-induced HF.Methods: Male Sprague-Dawley rats were randomly divided into the HF group and the sham-operated group. HF was induced by the transverse aortic constriction (TAC) surgery. The cardiac expression profiles of mRNAs and lncRNAs in HF were investigated using the microarray. Bioinformatics analyses and co-expression network construction were performed from the RNA sequencing data.Results: The expression profiles of mRNAs and lncRNAs showed significant differences between HF and controls. A total of 147 mRNAs and 162 lncRNAs were identified to be differentially expressed with a fold change of >2 in HF. The relative expression levels of several selected mRNAs and lncRNAs were validated by quantitative PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that diverse pathways were involved in the molecular mechanisms of cardiac hypertrophy and HF including immune response, smooth muscle contraction, ion transmembrane transport. The mRNA-lncRNA and transcription factors (TFs)-lncRNA co-expression networks were constructed and several genes and TFs were identified as key regulators in the pathogenesis of HF. Further functional prediction showed that the lncRNA NONRATT013999 was predicted to cis-regulate mRNA CDH11, and NONRATT027756 was predicted to trans-regulate HCN4.Conclusion: This study revealed specific expression regulation and potential functions of mRNAs and lncRNAs in pressure overload-induced HF. These results will provide new insights into the underlying mechanisms and potential therapeutic targets for HF.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Chen

Xue

et al. 2019

Front. Genet.

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“…Isolation of single cardiac cells was carried out in a modified Langendorff system by the method of Liao and Jain as described previously [13] and adapted by us [12]. Prior to dissection and cannulation of the heart, the perfusion system was filled with perfusion solution and cleared off any air bubbles.…”

Section: Cardiomyocyte Isolationmentioning

confidence: 99%

“…As previously described [12], the experimental chamber was mounted on an inverted microscope (Olympus OSP-3 photomultiplier system, Olympus, Tokyo, Japan). After the incubation with Fluo-4 AM, every petri dish was positioned on the experimental chamber and was filled TB-B solution.…”

Section: Fluorescence Measurementsmentioning

confidence: 99%

“…Calibration procedure for converting the voltage signal to Ca 2+ concentration was performed at the end of every experiment as previously described [10][11][12]. Briefly, the background of the petri dish was recorded in 10 different spots (no cells).…”

Section: Calibrationmentioning

confidence: 99%

“…Therefore, we hypothesized that known mepivacaine's effect on I Na might cause a reduction of Ca 2+ transient at the IC 50 for isolated murine cardiomyocyte, explaining the negative inotropic effect of mepivacaine previously described. To test this hypothesis we analyzed Ca 2+ transients' biophysical parameters established in our laboratory [10][11][12]. We observed in isolated adult mouse ventricular cardiomyocytes that mepivacaine's effect at the IC 50 calculated from the dose-response analysis, which is considered supra-clinical in humans, significantly reduced Ca 2+ release from the sarcoplasmic reticulum.…”

Section: Introductionmentioning

confidence: 99%

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Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes

2020

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Background: The potential mechanism of mepivacaine's myocardial depressant effect observed in papillary muscle has not yet been investigated at cellular level. Therefore, we evaluated mepivacaine's effects on Ca 2+ transient in isolated adult mouse cardiomyocytes. Methods: Single ventricular myocytes were enzymatically isolated from wild-type C57Bl/6 mice and loaded with 10 μM fluorescent Ca 2+ indicator Fluo-4-AM to record intracellular Ca 2+ transients upon electrical stimulation. The mepivacaine effects at half-maximal inhibitory concentration (IC 50) was determined on calibrated cardiomyocytes' Ca 2+ transients by non-parametric statistical analyses on biophysical parameters. Combination of mepivacaine with NCX blockers ORM-10103 or NiCl 2 were used to test a possible mechanism to explain mepivacaine-induced Ca 2+ transients' reduction. Results: A significant inhibition at mepivacaine's IC 50 (50 μM) on Ca 2+ transients was measured in biophysical parameters such as peak (control: 528.6 ± 73.61 nM vs mepivacaine: 130.9 ± 15.63 nM; p < 0.05), peak area (control: 401.7 ± 63.09 nM*s vs mepivacaine: 72.14 ± 10.46 nM*s; p < 0.05), slope (control: 7699 ± 1110 nM/s vs mepivacaine: 1686 ± 226.6 nM/s; p < 0.05), time to peak (control: 107.9 ± 8.967 ms vs mepivacaine: 83.61 ± 7.650 ms; p < 0.05) and D 50 (control: 457.1 ± 47.16 ms vs mepivacaine: 284.5 ± 22.71 ms; p < 0.05). Combination of mepivacaine with NCX blockers ORM-10103 or NiCl 2 showed a significant increase in the baseline of [Ca 2+ ] and arrhythmic activity upon electrical stimulation. Conclusion: At cellular level, mepivacaine blocks Na + channels, enhancing the reverse mode activity of NCX, leading to a significant reduction of Ca 2+ transients. These results suggest a new mechanism for the mepivacainereduction contractility effect.

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Cardiomyocyte depolarization triggers NOS-dependent NO transient after calcium release, reducing the subsequent calcium transient

et al. 2021

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Cardiac excitation–contraction coupling and metabolic and signaling activities are centrally modulated by nitric oxide (NO), which is produced by one of three NO synthases (NOSs). Despite the significant role of NO in cardiac Ca2+ homeostasis regulation under different pathophysiological conditions, such as Duchenne muscular dystrophy (DMD), no precise method describes the production, source or effect of NO through two NO signaling pathways: soluble guanylate cyclase-protein kinase G (NO-sGC-PKG) and S-nitrosylation (SNO). Using a novel strategy involving isolated murine cardiomyocytes loaded with a copper-based dye highly specific for NO, we observed a single transient NO production signal after each electrical stimulation event. The NO transient signal started 67.5 ms after the beginning of Rhod-2 Ca2+ transient signal and lasted for approximately 430 ms. Specific NOS isoform blockers or NO scavengers significantly inhibited the NO transient, suggesting that wild-type (WT) cardiomyocytes produce nNOS-dependent NO transients. Conversely, NO transient in mdx cardiomyocyte, a mouse model of DMD, was dependent on inducible NOS (iNOS) and endothelial (eNOS). In a consecutive stimulation protocol, the nNOS-dependent NO transient in WT cardiomyocytes significantly reduced the next Ca2+ transient via NO-sGC-PKG. In mdx cardiomyocytes, this inhibitory effect was iNOS- and eNOS-dependent and occurred through the SNO pathway. Basal NO production was nNOS- and iNOS-dependent in WT cardiomyocytes and eNOS- and iNOS-dependent in mdx cardiomyocytes. These results showed cardiomyocyte produces NO isoform-dependent transients upon membrane depolarization at the millisecond time scale activating a specific signaling pathway to negatively modulate the subsequent Ca2+ transient.

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Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

Cited by 27 publications

References 57 publications

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes

Cardiomyocyte depolarization triggers NOS-dependent NO transient after calcium release, reducing the subsequent calcium transient

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