Effect of high-dose cyclophosphamide gene expression profiles in cardiomyocytes of C57BL/6J mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE194073 | GEO | 2022/01/21
REPOSITORIES: GEO
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Project description:Background: Hyperphosphorylation of the calcium release channel/ryanodine receptor type 2 (RyR2) at serine 2814 (S2814) is associated with multiple cardiac diseases including atrial fibrilla-tion and heart failure. Despite recent advances, the molecular mechanisms driving pathological changes associated with RyR2 -S2814 phosphorylation are still not well understood. Methods: Using affinity-purification coupled to mass spectrometry (AP-MS), we investigated the RyR2 in-teractome in ventricles from wild-type (WT) mice and two S2814 knock-in mutants: the un-phosphorylated alanine mutant (S2814A) and hyperphosphorylated mimic aspartic acid mutant (S2814D). Western blots were used for validation. Results: In WT mouse ventricular lysates, we identified 22 proteins which were enriched with RyR2 pull-down relative to both IgG control and no antibody (beads-only) pull-downs. Parallel AP-MS using WT, S2814A, and S2814D mouse ventricles identified 72 proteins with 20 being high confident RyR2 interactors. Of these, 14 had an increase in their binding to RyR2 S2814A but a decrease in their binding to RyR2 S2814D. We independently validated three protein hits, Idh3b, Aifm1, and Cpt1b, as RyR2 interactors by western blot and showed that Aifm1 and Idh3b had significantly decreased binding to RyR2 S2814D compared to WT and S2814A, consistent with MS findings. Conclusion: By applying state-of-the-art proteomic approaches, we discovered a number of novel RyR2 interactors in the mouse heart. In addition, we found and defined specific alterations in the RyR2 interactome that were dependent on the phosphorylation status of RyR2 at S2814. These findings yield mechanistic insights into RyR2 regulation which may guide future drug designs.
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Project description:Purpose: Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca2+ is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we investigated whether pressure-overload induced hypertrophy can be induced by destabilization of cardiac ryanodine receptor (RyR2) through calmodulin (CaM) dissociation and subsequent Ca2+ leakage, and whether it can be genetically rescued by enhancing the binding affinity of CaM to RyR2. Methods: To examine the role of CaM-RyR2 complex in the development of pressure-overload induced cardiac hypertrophy, whole transcriptome analysis using RNA-seq analysis in the hearts from WT and homozygous RyR2V3599K/V3599K (V3599K) mice with or without transverse aortic constriction (TAC) was performed to elucidate the RyR2 signaling pathway in the heart. Results: Gene expression increased in WT (+TAC) hearts compared to WT (-TAC) hearts; however, this increase was not observed in V3599K (+TAC) hearts. Conclusions: Enhanced CaM binding to RyR2 decreased expression of hypertrophy-related genes.
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2021-12-14 | PXD021375 | Pride
Project description:This study addressed the assumption that in addition to somatic mutations epigenetic silencing of cancer-related genes by promoter hyper-methylation is a common event in head and neck cancer. A multi-scale omics approach based on whole-exome sequencing, global DNA methylation and gene expression profiling data derived from tumor samples of the HIPO-HNC cohort was conducted and new findings were confirmed with data from TCGA-HNC. Results provide experimental evidence that the ryanodine receptor 2 (RYR2) exhibits variable promoter methylation and expression in both tumor samples and HNSCC cell lines. Moreover, immunohistochemical staining of tissue sections unraveled a gradual loss of RYR2 expression from normal mucosa via dysplastic lesions to cancer, and indicated that reduced RYR2 expression in adjacent tissue and precancer lesions might serve as a risk factor for unfavorable prognosis and upcoming malignant conversion.
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Project description:This a model from the article:
Mechanisms of abnormal calcium homeostasis in mutations responsible for
catecholaminergic polymorphic ventricular tachycardia.
Iyer V, Hajjar RJ, Armoundas AA. Circ Res
2007 Feb 2;100(2):e22-31 17234962
,
Abstract:
Catecholaminergic polymorphic ventricular tachycardia is a heritable arrhythmia
unmasked by exertion or stress and is characterized by triggered activity and
sudden cardiac death. In this study, we simulated mutations in 2 genes linked to
catecholaminergic polymorphic ventricular tachycardia, the first located in
calsequestrin (CSQN2) and the second in the ryanodine receptor (RyR2). The aim
of the study was to investigate the mechanistic basis for spontaneous Ca2+
release events that lead to delayed afterdepolarizations in affected patients.
Sarcoplasmic reticulum (SR) luminal Ca2+ sensing was incorporated into a model
of the human ventricular myocyte, and CSQN2 mutations were modeled by simulating
disrupted RyR2 luminal Ca2+ sensing. In voltage-clamp mode, the mutant CSQN2
model recapitulated the smaller calcium transients, smaller time to peak calcium
transient, and accelerated recovery from inactivation seen in experiments. In
current clamp mode, in the presence of beta stimulation, we observed delayed
afterdepolarizations, suggesting that accelerated recovery of RyR2 induced by
impaired luminal Ca2+ sensing underlies the triggered activity observed in
mutant CSQN2-expressing myocytes. In current-clamp mode, in a model of mutant
RyR2 that is characterized by reduced FKBP12.6 binding to the RyR2 on beta
stimulation, the impaired coupled gating characteristic of these mutations was
modeled by reducing cooperativity of RyR2 activation. In current-clamp mode, the
mutant RyR2 model exhibited increased diastolic RyR2 open probability that
resulted in formation of delayed afterdepolarizations. In conclusion, these
minimal order models of mutant CSQN2 and RyR2 provide plausible mechanisms by
which defects in RyR2 gating may lead to the cellular triggers for arrhythmia,
with implications for the development of targeted therapy.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Iyer V, Hajjar RJ, Armoundas AA. (2007) - version=1.0
The original CellML model was created by:
Penny Noble
penny.noble@dpag.ox.ac.uk
The University of Oxford
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230030 | BioModels
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