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:The suppression mechanism of regulatory T cells (Tregs) is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by the transcription factor forkhead box P3 (FoxP3) expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca2+-release channel ryanodine receptor 2 (RyR2). Reduced RyR2 shuts down basal Ca2+ oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4+ T cell pool to become immune suppressive, and behave in the same manner as FoxP3+ Tregs in viral infection, asthma, hypersensitivity, colitis and tumor development. In the absence of FoxP3, RyR2-deficient CD4+ T cells (CKO) rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression.
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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:In cardiomyocytes, Ca2+ influx through L-type voltage-gated calcium channels (LTCCs) following membrane depolarization regulates crucial Ca2+-dependent processes including duration and amplitude of the action potentials and excitation-contraction coupling. LTCCs are heteromultimeric proteins composed of the Cav1, Cav, Cav2 and Cav subunits. Here, using ascorbate peroxidase (APEX)-mediated proximity labeling and quantitative proteomics, we identified 61 proteins in the nano-environments of Cav2 in cardiomyocytes. These proteins are involved in diverse cellular functions such as cellular trafficking, muscular contraction, sarcomere organization and excitation-contraction coupling. Moreover, pull-down assays, co-immunoprecipitation analyses and super-resolution imaging using direct stochastic optical reconstruction microscopy (dSTORM) revealed that Cav2 interacts with the ryanodine receptor 2 (RyR2) in adult cardiomyocytes, probably coupling LTCCs and the RyR2 into a supramolecular complex at the dyads. This interaction is mediated by the Src-homology 3 domain of Cav2 and is necessary for an effective pacing frequency‐dependent increase of the Ca2+-induced Ca2+ release mechanism in cardiomyocytes.
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Project description:Infiltration of peripheral immune cells after blood-brain barrier (BBB) dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans (GAGs), a component of the endothelial glycocalyx, in ischemic stroke were studied using a photochemically induced thrombosis (PIT) mouse model. As results, decreased levels of heparan sulfate (HS) and chondroitin sulfate (CS) and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine (NAC)+GAG oligosaccharides as compared to NAC administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by HBMEC/ciβ and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein exposure. We identified the ACR modified amino acid residues of proHPSE using nano LC-MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), and Lys107 and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part, is attributed to the activation of proHPSE. Since proHPSE, but not HPSE, localizes outside cells by binding with HS proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx.
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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.
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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
Project description:Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions. Here we found find that the stress kinases p38 and p38/are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that upon activation, the increased activity of p38 and p38/ was cooperatively associated increase the with susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38 and p38wphosphorylatee identified ryanodine receptor 2 (RyR2) and disrupt Kv4.3 channel localization, as a new substrate of p38/. Our data indicate that phosphorylation of SAP97 by activated p38/ also disrupts Kv4.3 localization at the plasma membrane, promoting sarcoplasmic reticulum calcium leak, Ito current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes, and enhanced susceptibility to VF. The importance of this finding is evidenced by the fact that bBlocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals. We have identified p38/-driven phosphorylation of RyR2 and SAP97 as a novel trigger of VF. These results indicate that p38 and p38/ are a new potential therapeutic target for sustained VF prevention.
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