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:Stretch and tachycardia are common triggers for cardiac remodelling in various conditions, but a comparative characterization of their role in the excitation-transcription coupling (ETC) and early regulation of gene expression and structural changes is lacking. Here, we show that stretch and tachycardia directly induced hypertrophy of neonatal rat cardiac myocytes and also of non-myocytes. Both triggers induced similar patterns of hypertrophy but had largely distinct gene expression profiles. ACTA1 served as good hypertrophy marker upon stretch, while RCAN1 was found increased in response to tachycardia in a rate-dependent fashion. Mechanistically, several calcium-handling proteins, including the sodium-calcium exchanger (NCX), contributed to ETC. Phosphorylation of the calcium/calmodulin-dependent protein kinase II (CaMKII) was elevated and occurred downstream of NCX activation upon tachycardia, but not stretch. Microarray profiling revealed that stretch and tachycardia regulated around 33% and 20% genes in a NCX-dependent manner, respectively. In conclusion, our data show that hypertrophy induction by stretch and tachycardia is associated with different gene expression profiles with a significant contribution of the NCX.
| S-EPMC7412684 | biostudies-literature
Project description:Excitation transcription coupling during acute stretch and tachycardia in non-failing human myocardium
| PRJNA557652 | ENA
Project description:Bulk RNA-Sequencing of EHTs subjected to tachypacing to probe the mechanism of tachycardia-induced cardiac dysfunction.
2023-11-17 | GSE242727 | GEO
Project description:While strongly implicated in Postural Tachycardia Syndrome (POTS), considerable controversy exists regarding norepinephrine transporter (NET) loss-of-function. POTS is characterized by the clinical symptoms of orthostatic intolerance, light-headedness, tachycardia and syncope or near syncope with upright posture. Abnormal sympathetic nervous system activity is typical, of a type which suggests dysfunction of the NET, with evidence the gene responsible is under tight epigenetic control. Using RNA of isolated chromatin combined with sequencing (RICh-Seq) we show let7i miRNA suppresses NET by MeCP2. Vorinostat restores epigenetic control and NET expression in POTS.
2017-01-07 | GSE93235 | GEO
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:Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients below 40 years of age. Familial clustering, early onset of symptoms, and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System.In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes.This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.
| EGAS00001002745 | EGA
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