The role of stretch, tachycardia and sodium-calcium exchanger in induction of early cardiac remodeling
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ABSTRACT:
PROVIDER: PRJNA557667 | ENA |
REPOSITORIES: ENA
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Project description:Accute stretch and tachycardia are capable of inducing pathological excitation transcription coupling - an early invent before structural cardiac remodeling which transitions to heart failure. The sodium calcium exchanger is a key player in maintaining calcium homeostasis and is implicated in pathological signaling during heart failure. Neonatal rat ventricular cardiomyocytes (NRVCM) were subjected to mechanical stress and high freqency elecrical stimulation to study genes regulated during the early phase of trigger induced cardiac remodeling. Inhibition of the sodium calcium exchanger was used in an attempt to supress the early remodeling process and gain insight into the pathological signaling pathway.
2020-08-12 | GSE135172 | GEO
Project description:Stretch increases wall stress and so far the molecular mechanisms behind increased afterload had been thouroughly studied in vitro and in vivo. Tachycardia when accutelly triggered has the potential to induce cardiac remodeling as stretch does. However the degree of response, similarities and differencess have not been adressed so far. We aimed to perform whole genome screening for genes that are affected by accute application of stretch and tachycardia in human non-failing tissue.
2022-01-01 | GSE135166 | GEO
Project description: Not available
| S-EPMC7412684 | biostudies-literature
Project description:In a patient with right ventricular outflow tract (RVOT) tachycardia we identified a heterozygous point mutation in the selectivity filter of the stretch-activated K2P potassium channel TREK-1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK-1 In addition, mutant channels exhibit a hypersensitivity to stretch-activation, suggesting that the selectivity filter is directly involved in stretch-induced activation and desensitization. Increased sodium permeability and stretch-sensitivity of mutant TREK-1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT. We present a pharmacological strategy to rescue the selectivity defect of the TREK-1 pore. Our findings provide important insights for future studies of K2P channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.
| EGAS00001002319 | EGA
Project description:Ferroptosis is an iron-dependent form of cell death driven by biochemical and metabolic alterations resulting in oxidation within the lipid compartment. Calcium is a potent signaling molecule ascribed to diverse cellular processes including migration, neurotransmitter function, and cell death. Here we elucidate a crucial link between calcium homeostasis and ferroptotic cell death through the identification of the tetraspanin MS4A15. Ectopic MS4A15 expression specifically protects against ferroptosis by depleting endoplasmic reticulum stores. In an unexpected connection, prolonged calcium dysregulation stimulates fundamental remodeling to ferroptosis-resistant monounsaturated and plasmalogen lipid species. Application of this discovery revealed that augmenting luminal calcium sensitizes cancer cell lines previously refractory to ferroptosis. This finding provides a unique mechanistic basis for ferroptosis sensitivity and resolves a long-standing query into the role of calcium in oxidative cell death. Manipulating calcium homeostasis offers an unprecedented strategy for overcoming therapy resistance in cancer.
2021-10-09 | GSE160574 | GEO
Project description:Excitation transcription coupling during acute stretch and tachycardia in non-failing human myocardium
| PRJNA557652 | ENA
Project description:The cardiac sodium–calcium exchanger (NCX1) is important for normal Na+ and Ca2+ homeostasis and cardiomyocyte relaxation and contraction. NCX1 activity is reduced by its endogenous inhibitor phosphorylated phospholemman (pSer68-PLM). Disrupting the pSer68-PLM-NCX1 interaction is therefore a potential therapeutic strategy to reverse NCX1 inhibition in cardiac disease. We have previously designed a high affinity NCX1-PLM disruptor peptide (OPT) that reverses the inhibitory pSer68-PLM-NCX1 interaction in HEK293 cells. In the present study, we performed N and C-terminal truncation analyses of OPT and identified PYKEIEQLIELANYQV as the minimal pSer68-PLM binding sequence. To increase peptide stability in human serum, we replaced the proline in its N-terminus with an N-methyl-proline (NOPT) after identification of N-terminus as substitution tolerant by two dimensional peptide array analysis. Mass spectrometry analysis revealed that the half-life of the novel NOPT peptide was increased 10-fold compared to that of OPT. Biotinylated NOPT pulled down endogenous PLM from rat left ventricle lysate and exhibited pSer68-PLM binding in an ELISA-based assay. Importantly, NOPT reduced the PLM-NCX1 interaction in an ELISA-based assay and cell permeable NOPT-TAT increased the NCX1 activity in adult cardiomyocytes isolated from both wild type (WT) and HF animals. Finally, we found that NOPT interacted with pSer68-PLM with a KD value of 2.7±3.8 μM, whereas the NCX1 cytoplasmic part interacted with PLM and pSer68-PLM with KD values of 14±2 nM and 24±14 nM. In conclusion, we have here developed a proteolytically stable NCX1-PLM disruptor peptide that upregulates NCX1 activity in WT and HF cardiomyocytes.
2021-09-09 | PXD022797 | Pride
Project description:The goal of this study was to examine the effect of the major axis of biaxial mechanical stretch on cardiac myocyte gene expression and to identify the signaling pathways and transcription factors regulating these changes. Neonatal cardiac myocytes were cultured on a micropatterned substrate, and the primary stretch axis was applied either parallel or transverse to the myofibril direction. RNA sequencing was conducted to study whole genomic expression changes after acute cardiac myocyte stretch. The results showed a more robust gene response to longitudinal than to transverse stretch. After 30 minutes of stretch, 53 and 168 genes were considered differentially expressed (DE) from transverse and longitudinal stretch, respectively. After 4 hours, the number of DE genes increased to 795 in longitudinal stretch while it decreased to 35 in transverse stretch. Gene ontology term (GO) analysis indicated enrichment of TF activity and protein kinase activity by both stretch axes; whereas longitudinal but not transverse stretch caused expression of genes involved in sarcomere organization and cytoskeletal protein binding.
2019-06-01 | GSE83655 | GEO
Project description:Zebrafish ncx1h (also known as slc8a1a) encodes a cardiac specific sodium-calcium exchanger 1 (NCX1h), a primary Ca 2+ efflux effector in cardiomyocytes. The zebrafish tremblor (tre) mutant lacks functional NCX1h and, consequentially, cyclic Ca2+ transients are abolished. In this study, we investigated the effect of aberrant Ca2+ homeostasis in cardiomyocytes on gene expression. Wild type and ncx1 mutant hearts at 48 hours post fertilization were isolated for RNA preparation and gene expression analysis was performed using an Affymetrix Zebrafish GeneChip.
2017-09-20 | E-MTAB-5850 | biostudies-arrayexpress
Project description:We profiled the transcriptomes of 4 human lung cell types that were subjected to control (non-stretch) and 30% tonic stretch conditions for 4 hours and 24 hours.
2016-04-12 | GSE80161 | GEO