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Iyer2007_Arrhythmia_CardiacDeath

ABSTRACT: 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. . 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.

SUBMITTER: Camille Laibe

PROVIDER: MODEL1006230030 | BioModels | 2005-01-01

REPOSITORIES: BioModels

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Publications

Mechanisms of abnormal calcium homeostasis in mutations responsible for catecholaminergic polymorphic ventricular tachycardia.

Iyer Vivek V Hajjar Roger J RJ Armoundas Antonis A AA

Circulation research 20070118 2

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 del ...[more]

PMID: 17234962

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Project description:Lamin A/C proteins, encoded by the LMNA gene, are intermediate filament proteins of the nuclear lamina, and predominantly expressed in differentiated cells including cardiomyocytes. Mutations in LMNA are associated with laminopathies, congenital diseases affecting muscle and homeostasis. One of the laminopathies associated with a missense mutation (N195K) in the A-type lamins results in dilated cardiomyopathy (DCM) with arrhythmias and sudden death. However it is unknown how the mutation in this LMNA gene contributes to the mechanism of arrhythmia and sudden death. To investigate this a mouse line expressing the Lmna-N195K (LmnaN195K/N195K) was used. Mutant mice demonstrated reduced fractional shortening, LV mass, wall thickness and dilated cardiomyopathy by echocardiography at 6 weeks consistent with human DCM, and died at an early age (6-7 weeks). Comparative cDNA microarray analysis from LmnaN195K/N195K and the wild type (WT) control ventricles at 6 weeks age revealed significant alterations in the expression of ion channels, transporter proteins, caveolins and associated proteins such as MAP kinases. Transmission electron microscopy analysis showed structural alterations of the ventricular myocytes with increase in number of caveolae. Quantitative Western blot analysis confirmed reduced expression for Cavβ (2 fold) subunits of the L-type Ca2+ channel. In contrast the expression levels of Cav3 (2.5 fold) was significantly increased. To investigate the functional impact of Lmna N195K on the ICa,L, we transiently expressed either the WT LMNA+GFP, Lmna N195K+GFP or GFP (control) in isolated neonatal mouse ventricular myocytes and performed whole cell patch clamp analysis. Transient expression of Lmna N195K significantly reduced (58 %) peak ICa,L (-6.0 ± 2 pA/pF, n=9) compared to GFP control (-14 ± 2 pA/pF, n=8). Expression of WT LMNA did not affect the ICa,L (-14.2 ± 2.5 pA/pF, n=8) compared to control. Conclusion: We conclude that Lmna N195K mutation results in reduced expression of ion channels and scaffolding proteins in the left ventricle with a significant reduction in peak ICa,L in ventricular myocytes and these may contribute to the mechanism of arrhythmia and dilated cardiomyopathy. 6 samples

Project description:PAO1 was cultured planktonically to stationary phase with 10 mM calcium and no added calcium. The transcriptional response to calcium addition was determined. Pseudomonas aeruginosa is an opportunistic human pathogen that causes severe, life threatening infections in patients with cystic fibrosis (CF), endocarditis, wounds, or with artificial implants. During CF pulmonary infections, P. aeruginosa often encounters environments where the levels of calcium (Ca2+) are elevated. Previously, we showed that P. aeruginosa responds to externally added Ca2+ through enhanced biofilm formation, increased production of several secreted virulence factors, and by developing a transient increase in the intracellular Ca2+ followed by its removal to the basal sub-micromolar level. However, the molecular mechanisms responsible for regulating Ca2+-induced virulence factor production and Ca2+ homeostasis are not known. Here, we characterized the genome-wide transcriptional response of P. aeruginosa strains PAO1 and FRD1 to elevated [Ca2+] in both planktonic cultures and in biofilms. Among the genes induced by CaCl2 in PAO1 was an operon containing the two-component regulator PA2656-PA2657 (here called carS and carR), while the closely related two-component regulators, phoPQ and pmrAB were repressed by CaCl2 addition. To identify the regulatory targets of CarSR, we constructed a deletion mutant of carR, and performed transcriptome analysis of the mutant strain at low and high [Ca2+]. Among the genes regulated by CarSR in response to CaCl2 are the predicted periplasmic OB-fold protein, PA0320 and the inner membrane-anchored five-bladed -propeller protein, PA0327. Mutations in both PA0320 and PA0327 affected Ca2+ homeostasis, reducing the ability of P. aeruginosa to export excess Ca2+. In addition, a mutation in PA0327 had a pleotrophic effect in a Ca2+-dependent manner, altering swarming motility, pyocyanin production, and tobramycin sensitivity. Overall, the results indicate that the two-component system CarSR is responsible for sensing high levels of external Ca2+, and responding through its regulatory targets that modulate Ca2+ homeostasis, surface-associated motility, and production of the virulence factor, pyocyanin.

Project description:PAO1 and FRD1 were cultured planktonically and in biofilms with 10 mM calcium and no added calcium. The transcriptional response to calcium addition was determined for PAO1 cultured planktonically, for FRD1 cultured planktonically, for PAO1 cutured in biofilms, and for FRD1 cultured in biofilms. Pseudomonas aeruginosa is an opportunistic human pathogen that causes severe, life threatening infections in patients with cystic fibrosis (CF), endocarditis, wounds, or with artificial implants. During CF pulmonary infections, P. aeruginosa often encounters environments where the levels of calcium (Ca2+) are elevated. Previously, we showed that P. aeruginosa responds to externally added Ca2+ through enhanced biofilm formation, increased production of several secreted virulence factors, and by developing a transient increase in the intracellular Ca2+ followed by its removal to the basal sub-micromolar level. However, the molecular mechanisms responsible for regulating Ca2+-induced virulence factor production and Ca2+ homeostasis are not known. Here, we characterized the genome-wide transcriptional response of P. aeruginosa strains PAO1 and FRD1 to elevated [Ca2+] in both planktonic cultures and in biofilms. Among the genes induced by CaCl2 in PAO1 was an operon containing the two-component regulator PA2656-PA2657 (here called carS and carR), while the closely related two-component regulators, phoPQ and pmrAB were repressed by CaCl2 addition. To identify the regulatory targets of CarSR, we constructed a deletion mutant of carR, and performed transcriptome analysis of the mutant strain at low and high [Ca2+]. Among the genes regulated by CarSR in response to CaCl2 are the predicted periplasmic OB-fold protein, PA0320 and the inner membrane-anchored five-bladed -propeller protein, PA0327. Mutations in both PA0320 and PA0327 affected Ca2+ homeostasis, reducing the ability of P. aeruginosa to export excess Ca2+. In addition, a mutation in PA0327 had a pleotrophic effect in a Ca2+-dependent manner, altering swarming motility, pyocyanin production, and tobramycin sensitivity. Overall, the results indicate that the two-component system CarSR is responsible for sensing high levels of external Ca2+, and responding through its regulatory targets that modulate Ca2+ homeostasis, surface-associated motility, and production of the virulence factor, pyocyanin.

Project description:The LEF/TCF family of transcription factors are downstream effectors of the WNT signaling pathway, which drives colon tumorigenesis. LEF/TCFs have a DNA sequence-specific HMG box that binds Wnt Response Elements (WREs). The “E tail” isoforms of TCFs are alternatively spliced to include a second DNA binding domain called the C-clamp. We show that induction of a dominant negative C-clamp version of TCF1 (dnTCF1E) induces a p21-dependent stall in the growth of DLD1 colon cancer cells. Induction of a C-clamp mutant did not induce p21 or stall cell growth. Microarray analysis revealed that induction of p21 by dnTCF1EWT correlated with a decrease in expression of p21 suppressors that act at multiple levels from transcription (SP5, YAP1, RUNX1), to RNA stability (MSI2), and protein stability (CUL4A). We show that the C-clamp is a sequence specific DNA binding domain that can make contacts with 5’-RCCG-3’ elements upstream or downstream of WREs. The C-clamp-RCCG interaction was critical for TCF1E mediated transcriptional control of p21-connected target gene promoters. Our results indicate that a WNT/p21 circuit is driven by C-clamp target gene selection. Gene expression analysis of dnTCF and dnLEF induction in colon cancer cells. Dominant negative LEF/TCFs interferes with endogenous Wnt signaling by binding to Wnt Response Elements of target genes and displacing beta-catenin. Here we used induction of dnTCF-1 (wildtype and mutant forms of the C-clamp DNA binding domain) and dnLEF-1 to identify genes that change expression at 8 hours and 23 hours post-induction. Three DLD-1 clonal stable cell lines created by tetracycline-regulated expression (T-REx) system were treated with or without doxycycline for RNA extraction and hybridization on Affymetrix microarrays. One of the three cell lines is a mock cell line,a parental cell line that expresses only the Tet regulator and does not overexpress any protein when induced with doxycycline (Dox). The other three cell lines can be induced by Doxycycline to overexpress wild-type dnTCF-1E or a mutant form of dnTCF-1E with five amino acid substitution mutations in the C-clamp of the E-tail, or dnLEF-1. The mock cell line and dnLEF-1 cell lines were treated with or without Dox for 23 hr. The wild-type and mutant dnTCF-1E cell lines were treated with or without Dox for 8 and 23 hr, and as well, wild-type dnTCF-1E was induced with maximal amounts of Dox (hi: 1ug/ml) for maximum expression and gene expression regulation.

Project description:This a model from the article: The functional role of cardiac T-tubules explored in a model of rat ventricular myocytes. Pásek M, Simurda J, Christé G. Philos Transact A Math Phys Eng Sci. 2006 May 15;364(1842):1187-206. 16608703 , Abstract: The morphology of the cardiac transverse-axial tubular system (TATS) has been known for decades, but its function has received little attention. To explore the possible role of this system in the physiological modulation of electrical and contractile activity, we have developed a mathematical model of rat ventricular cardiomyocytes in which the TATS is described as a single compartment. The geometrical characteristics of the TATS, the biophysical characteristics of ion transporters and their distribution between surface and tubular membranes were based on available experimental data. Biophysically realistic values of mean access resistance to the tubular lumen and time constants for ion exchange with the bulk extracellular solution were included. The fraction of membrane in the TATS was set to 56%. The action potentials initiated in current-clamp mode are accompanied by transient K+ accumulation and transient Ca2+ depletion in the TATS lumen. The amplitude of these changes relative to external ion concentrations was studied at steady-state stimulation frequencies of 1-5 Hz. Ca2+ depletion increased from 7 to 13.1% with stimulation frequency, while K+ accumulation decreased from 4.1 to 2.7%. These ionic changes (particularly Ca2+ depletion) implicated significant decrease of intracellular Ca2+ load at frequencies natural for rat heart. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Pásek M, Simurda J, Christé G. (2006) - version03 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@aukland.ac.nz The University of Auckland The Bioengineering Institute 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.. 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.

Dataset Information

Iyer2007_Arrhythmia_CardiacDeath

Publications

Mechanisms of abnormal calcium homeostasis in mutations responsible for catecholaminergic polymorphic ventricular tachycardia.

Similar Datasets

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