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Article ; Online: Deficiency of heme oxygenase 1a causes detrimental effects on cardiac function.

Wang, Hong / Siren, Juuso / Perttunen, Sanni / Immonen, Katariina / Chen, Yu-Chia / Narumanchi, Suneeta / Kosonen, Riikka / Paavola, Jere / Laine, Mika / Tikkanen, Ilkka / Lakkisto, Päivi

Journal of cellular and molecular medicine

2024 Volume 28, Issue 7, Page(s) e18243

Abstract: Humans lacking heme oxygenase 1 (HMOX1) display growth retardation, haemolytic anaemia, and vulnerability to stress; however, cardiac function remains unclear. We aimed to explore the cardiac function of zebrafish lacking hmox1a at baseline and in ... ...

Abstract	Humans lacking heme oxygenase 1 (HMOX1) display growth retardation, haemolytic anaemia, and vulnerability to stress; however, cardiac function remains unclear. We aimed to explore the cardiac function of zebrafish lacking hmox1a at baseline and in response to stress. We generated zebrafish hmox1a mutants using CRISPR/Cas9 genome editing technology. Deletion of hmox1a increases cardiac output and further induces hypertrophy in adults. Adults lacking hmox1a develop myocardial interstitial fibrosis, restrain cardiomyocyte proliferation and downregulate renal haemoglobin and cardiac antioxidative genes. Larvae lacking hmox1a fail to respond to hypoxia, whereas adults are insensitive to isoproterenol stimulation in the heart, suggesting that hmox1a is necessary for cardiac response to stress. Haplodeficiency of hmox1a stimulates non-mitochondrial respiration and cardiac cell proliferation, increases cardiac output in larvae in response to hypoxia, and deteriorates cardiac function and structure in adults upon isoproterenol treatment. Intriguingly, haplodeficiency of hmox1a upregulates cardiac hmox1a and hmox1b in response to isoproterenol. Collectively, deletion of hmox1a results in cardiac remodelling and abrogates cardiac response to hypoxia and isoproterenol. Haplodeficiency of hmox1a aggravates cardiac response to the stress, which could be associated with the upregulation of hmox1a and hmox1b. Our data suggests that HMOX1 homeostasis is essential for maintaining cardiac function and promoting cardioprotective effects.
MeSH term(s)	Animals ; Humans ; Heme Oxygenase (Decyclizing) ; Zebrafish/genetics ; Isoproterenol/pharmacology ; Heme Oxygenase-1/genetics ; Myocardium ; Cardiomyopathies ; Hypoxia ; Myocytes, Cardiac
Chemical Substances	Heme Oxygenase (Decyclizing) (EC 1.14.14.18) ; Isoproterenol (L628TT009W) ; Heme Oxygenase-1 (EC 1.14.14.18)
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.18243
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Article: Zebrafish Heart Failure Models.

Narumanchi, Suneeta / Wang, Hong / Perttunen, Sanni / Tikkanen, Ilkka / Lakkisto, Päivi / Paavola, Jere

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 662583

Abstract: Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete. Zebrafish has proven useful for modeling human heart diseases due to similarity of ... ...

Abstract	Heart failure causes significant morbidity and mortality worldwide. The understanding of heart failure pathomechanisms and options for treatment remain incomplete. Zebrafish has proven useful for modeling human heart diseases due to similarity of zebrafish and mammalian hearts, fast easily tractable development, and readily available genetic methods. Embryonic cardiac development is rapid and cardiac function is easy to observe and quantify. Reverse genetics, by using morpholinos and CRISPR-Cas9 to modulate gene function, make zebrafish a primary animal model for
Language	English
Publishing date	2021-05-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.662583
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Article: Generation of the Human Pluripotent Stem-Cell-Derived Astrocyte Model with Forebrain Identity.

Peteri, Ulla-Kaisa / Pitkonen, Juho / Utami, Kagistia Hana / Paavola, Jere / Roybon, Laurent / Pouladi, Mahmoud A / Castrén, Maija L

Brain sciences

2021 Volume 11, Issue 2

Abstract: Astrocytes form functionally and morphologically distinct populations of cells with brain-region-specific properties. Human pluripotent stem cells (hPSCs) offer possibilities to generate astroglia for studies investigating mechanisms governing the ... ...

Abstract	Astrocytes form functionally and morphologically distinct populations of cells with brain-region-specific properties. Human pluripotent stem cells (hPSCs) offer possibilities to generate astroglia for studies investigating mechanisms governing the emergence of astrocytic diversity. We established a method to generate human astrocytes from hPSCs with forebrain patterning and final specification with ciliary neurotrophic factor (CNTF). Transcriptome profiling and gene enrichment analysis monitored the sequential expression of genes determining astrocyte differentiation and confirmed activation of forebrain differentiation pathways at Day 30 (D30) and D60 of differentiation in vitro. More than 90% of astrocytes aged D95 in vitro co-expressed the astrocytic markers glial fibrillary acidic protein (GFAP) and S100β. Intracellular calcium responses to ATP indicated differentiation of the functional astrocyte population with constitutive monocyte chemoattractant protein-1 (MCP-1/CCL2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) expression. The method was reproducible across several hPSC lines, and the data demonstrated the usefulness of forebrain astrocyte modeling in research investigating forebrain pathology.
Language	English
Publishing date	2021-02-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci11020209
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Article ; Online: Genetic and functional implications of an exonic TRIM55 variant in heart failure.

Heliste, Juho / Chheda, Himanshu / Paatero, Ilkka / Salminen, Tiina A / Akimov, Yevhen / Paavola, Jere / Elenius, Klaus / Aittokallio, Tero

Journal of molecular and cellular cardiology

2019 Volume 138, Page(s) 222–233

Abstract: Background: To tackle the missing heritability of sporadic heart failure, we screened for novel heart failure-associated genetic variants in the Finnish population and functionally characterized a novel variant in vitro and in vivo.: Methods and ... ...

Abstract	Background: To tackle the missing heritability of sporadic heart failure, we screened for novel heart failure-associated genetic variants in the Finnish population and functionally characterized a novel variant in vitro and in vivo. Methods and results: Heart failure-associated variants were screened in genotyping array data of the FINRISK study, consisting of 994 cases and 20,118 controls. Based on logistic regression analysis, a potentially damaging variant in TRIM55 (rs138811034), encoding an E140K variant, was selected for validations. In HL-1 cardiomyocytes, we used CRISPR/Cas9 technology to introduce the variant in the endogenous locus, and additionally TRIM55 wildtype or E140K was overexpressed from plasmid. Functional responses were profiled using whole-genome RNA sequencing, RT-PCR and Western analyses, cell viability and cell cycle assays and cell surface area measurements. In zebrafish embryos, cardiac contractility was measured using videomicroscopy after CRISPR-mediated knockout of trim55a or plasmid overexpression of TRIM55 WT or E140K. Genes related to muscle contraction and cardiac stress were highly regulated in Trim55 E140K/- cardiomyocytes. When compared to the WT/WT cells, the variant cells demonstrated reduced viability, significant hypertrophic response to isoproterenol, p21 protein overexpression and impaired cell cycle progression. In zebrafish embryos, the deletion of trim55a or overexpression of TRIM55 E140K reduced cardiac contractility as compared to embryos with wildtype genotype or overexpression of WT TRIM55, respectively. Conclusions: A previously uncharacterized TRIM55 E140K variant demonstrated a number of functional implications for cardiomyocyte functions in vitro and in vivo. These findings suggest a novel role for TRIM55 polymorphism in predisposing to heart failure.
MeSH term(s)	Actinin/metabolism ; Animals ; Base Sequence ; Calcium/metabolism ; Cardiomegaly/complications ; Cardiomegaly/genetics ; Cardiomegaly/pathology ; Cell Cycle ; Cell Line ; Cell Survival ; Chromosomes, Human, Pair 8/genetics ; Cohort Studies ; Embryo, Nonmammalian/metabolism ; Exons/genetics ; Finland ; Gene Expression Regulation ; Genetic Variation ; Heart Failure/genetics ; Heart Failure/physiopathology ; Humans ; Myocardial Contraction/genetics ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Sequestosome-1 Protein/metabolism ; Serum Response Factor/metabolism ; Stress, Physiological/genetics ; Tripartite Motif Proteins/genetics ; Zebrafish/embryology
Chemical Substances	SQSTM1 protein, human ; Sequestosome-1 Protein ; Serum Response Factor ; TRIM55 protein, human ; Tripartite Motif Proteins ; Actinin (11003-00-2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-12-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2019.12.008
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Article ; Online: A vertebrate model for the study of lipid binding/transfer protein function: conservation of OSBP-related proteins between zebrafish and human.

Zhou, You / Wohlfahrt, Gerd / Paavola, Jere / Olkkonen, Vesa M

Biochemical and biophysical research communications

2014 Volume 446, Issue 3, Page(s) 675–680

Abstract: Oxysterol-binding protein (OSBP) and OSBP-related (ORP) or OSBP-like (OSBPL) proteins constitute a family of lipid-binding/transfer proteins (LTPs) present in eukaryotes from yeast to man. The mechanisms of ORP function have remained incompletely ... ...

Abstract	Oxysterol-binding protein (OSBP) and OSBP-related (ORP) or OSBP-like (OSBPL) proteins constitute a family of lipid-binding/transfer proteins (LTPs) present in eukaryotes from yeast to man. The mechanisms of ORP function have remained incompletely understood. However, several ORPs are present at membrane contact sites and act as either lipid transporters or sensors that control lipid metabolism, cell signaling, and vesicle transport. Zebrafish, Danio rerio, has gained increasing popularity as a model organism in developmental biology, human disease, toxicology, and drug discovery. However, LTPs in the fish are thus far unexplored. In this article we report a series of bioinformatic analyses showing that the OSBPL gene family is highly conserved between the fish and human. The OSBPL subfamily structure is markedly similar between the two organisms, and all 12 human genes have orthologs, designated osbpl and located on 11 chromosomes in D. rerio. Interestingly, osbpl2 and osbpl3 are present as two closely related homologs (a and b), due to gene duplication events in the teleost lineage. Moreover, the domain structures of the distinct ORP proteins are almost identical between zebrafish and man, and molecular modeling in the present study suggests that ORD liganding by phosphatidylinositol-4-phosphate (PI4P) is a feature conserved between yeast Osh3p, human ORP3, and zebrafish Osbpl3. The present analysis identifies D. rerio as an attractive model to study the functions of ORPs in vertebrate development and metabolism.
MeSH term(s)	Amino Acid Sequence ; Animals ; Carrier Proteins/metabolism ; Conserved Sequence ; Glycerophospholipids/metabolism ; Humans ; Lipid Metabolism ; Phosphatidylinositol Phosphates/metabolism ; Protein Conformation ; Protein Structure, Tertiary ; Receptors, Steroid/metabolism ; Zebrafish Proteins/chemistry ; Zebrafish Proteins/metabolism
Chemical Substances	Carrier Proteins ; Glycerophospholipids ; OSBPL2 protein, human ; OSBPL3 protein, human ; Phosphatidylinositol Phosphates ; Receptors, Steroid ; Zebrafish Proteins ; phosphatidylinositol 4-phosphate
Language	English
Publishing date	2014-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2013.12.002
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Zs.A 116: Show issues

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Article: A vertebrate model for the study of lipid binding/transfer protein function: Conservation of OSBP-related proteins between zebrafish and human

Zhou, You / Wohlfahrt, Gerd / Paavola, Jere / Olkkonen, Vesa M

Biochemical and biophysical research communications. 2014 Apr. 11, v. 446

2014

Abstract	Oxysterol-binding protein (OSBP) and OSBP-related (ORP) or OSBP-like (OSBPL) proteins constitute a family of lipid-binding/transfer proteins (LTPs) present in eukaryotes from yeast to man. The mechanisms of ORP function have remained incompletely understood. However, several ORPs are present at membrane contact sites and act as either lipid transporters or sensors that control lipid metabolism, cell signaling, and vesicle transport. Zebrafish, Danio rerio, has gained increasing popularity as a model organism in developmental biology, human disease, toxicology, and drug discovery. However, LTPs in the fish are thus far unexplored. In this article we report a series of bioinformatic analyses showing that the OSBPL gene family is highly conserved between the fish and human. The OSBPL subfamily structure is markedly similar between the two organisms, and all 12 human genes have orthologs, designated osbpl and located on 11 chromosomes in D. rerio. Interestingly, osbpl2 and osbpl3 are present as two closely related homologs (a and b), due to gene duplication events in the teleost lineage. Moreover, the domain structures of the distinct ORP proteins are almost identical between zebrafish and man, and molecular modeling in the present study suggests that ORD liganding by phosphatidylinositol-4-phosphate (PI4P) is a feature conserved between yeast Osh3p, human ORP3, and zebrafish Osbpl3. The present analysis identifies D. rerio as an attractive model to study the functions of ORPs in vertebrate development and metabolism.
Keywords	Danio rerio ; bioinformatics ; chromosomes ; drugs ; eukaryotic cells ; fish ; gene duplication ; genes ; human diseases ; humans ; lipid metabolism ; lipids ; molecular models ; physiological transport ; toxicology ; transporters ; yeasts
Language	English
Dates of publication	2014-0411
Size	p. 675-680.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2013.12.002
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Article ; Online: Sept7b

Dash, Surjya Narayan / Narumanchi, Suneeta / Paavola, Jere / Perttunen, Sanni / Wang, Hong / Lakkisto, Päivi / Tikkanen, Ilkka / Lehtonen, Sanna

American journal of physiology. Heart and circulatory physiology

2017 Volume 312, Issue 5, Page(s) H1085–H1095

Abstract: Myofibrils made up of actin, myosin, and associated proteins generate the contractile force in muscle, and, consequently, mutations in these proteins may lead to heart failure. Septins are a conserved family of small GTPases that associate with actin ... ...

Abstract	Myofibrils made up of actin, myosin, and associated proteins generate the contractile force in muscle, and, consequently, mutations in these proteins may lead to heart failure. Septins are a conserved family of small GTPases that associate with actin filaments, microtubules, and cellular membranes. Despite the importance of septins in cytoskeleton organization, their role in cardiomyocyte organization and function is poorly characterized. Here, we show that septin 7 is expressed in both embryonic and adult zebrafish hearts and elucidate the physiological significance of
MeSH term(s)	Actin Cytoskeleton/metabolism ; Animals ; Morphogenesis/physiology ; Muscle Cells/physiology ; Septins/metabolism ; Subcellular Fractions/metabolism ; Ventricular Function/physiology ; Zebrafish/physiology ; Zebrafish Proteins/metabolism
Chemical Substances	Sept7b protein, zebrafish ; Zebrafish Proteins ; Septins (EC 3.6.1.-)
Language	English
Publishing date	2017-03-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00394.2016
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Article ; Online: Inhibition of

Narumanchi, Suneeta / Kalervo, Karri / Perttunen, Sanni / Wang, Hong / Immonen, Katariina / Kosonen, Riikka / Laine, Mika / Ruskoaho, Heikki / Tikkanen, Ilkka / Lakkisto, Päivi / Paavola, Jere

Journal of cardiovascular development and disease

2019 Volume 6, Issue 2

Abstract: ... ...

Abstract	The
Language	English
Publishing date	2019-04-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2777082-5
ISSN	2308-3425 ; 2308-3425
ISSN (online)	2308-3425
ISSN	2308-3425
DOI	10.3390/jcdd6020016
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Article ; Online: Vezf1 regulates cardiac structure and contractile function.

Paavola, Jere / Alakoski, Tarja / Ulvila, Johanna / Kilpiö, Teemu / Sirén, Juuso / Perttunen, Sanni / Narumanchi, Suneeta / Wang, Hong / Lin, Ruizhu / Porvari, Katja / Junttila, Juhani / Huikuri, Heikki / Immonen, Katariina / Lakkisto, Päivi / Magga, Johanna / Tikkanen, Ilkka / Kerkelä, Risto

EBioMedicine

2020 Volume 51, Page(s) 102608

Abstract: Background: Vascular endothelial zinc finger 1 (Vezf1) is a transcription factor previously shown to regulate vasculogenesis and angiogenesis. We aimed to investigate the role of Vezf1 in the postnatal heart.: Methods: The role of Vezf1 in regulating ...

Abstract	Background: Vascular endothelial zinc finger 1 (Vezf1) is a transcription factor previously shown to regulate vasculogenesis and angiogenesis. We aimed to investigate the role of Vezf1 in the postnatal heart. Methods: The role of Vezf1 in regulating cardiac growth and contractile function was studied in zebrafish and in primary cardiomyocytes. Findings: We find that expression of Vezf1 is decreased in diseased human myocardium and mouse hearts. Our experimental data shows that knockdown of zebrafish Vezf1 reduces cardiac growth and results in impaired ventricular contractile response to β-adrenergic stimuli. However, Vezf1 knockdown is not associated with dysregulation of cardiomyocyte Ca Interpretation: We demonstrate a role for Vezf1 in regulation of compensatory cardiac growth and cardiomyocyte contractile function, which may be relevant in human cardiac disease.
MeSH term(s)	Adrenergic Agents/pharmacology ; Animals ; Binding Sites ; Cardiomyopathies/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation/drug effects ; Genes, Reporter ; Humans ; Luciferases/metabolism ; Mice, Inbred C57BL ; Myocardial Contraction ; Myocardium/metabolism ; Myocardium/pathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myosin Heavy Chains/genetics ; Myosin Heavy Chains/metabolism ; Neovascularization, Physiologic/drug effects ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; Rats, Sprague-Dawley ; Transcription Factors/metabolism ; Zebrafish ; Zebrafish Proteins/metabolism
Chemical Substances	Adrenergic Agents ; DNA-Binding Proteins ; Transcription Factors ; VEZF1 protein, human ; Vezf1 protein, mouse ; Zebrafish Proteins ; vezf1b protein, zebrafish ; Luciferases (EC 1.13.12.-) ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2020-01-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2019.102608
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Zs.A 7090: Show issues

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Article ; Online: Antiarrhythmic Effects of Dantrolene in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia and Replication of the Responses Using iPSC Models.

Penttinen, Kirsi / Swan, Heikki / Vanninen, Sari / Paavola, Jere / Lahtinen, Annukka M / Kontula, Kimmo / Aalto-Setälä, Katriina

PloS one

2015 Volume 10, Issue 5, Page(s) e0125366

Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant inherited arrhythmogenic disorder. Type 1 CPVT (CPVT1) is caused by cardiac ryanodine receptor (RyR2) gene mutations resulting in abnormal calcium release from ... ...

Abstract	Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant inherited arrhythmogenic disorder. Type 1 CPVT (CPVT1) is caused by cardiac ryanodine receptor (RyR2) gene mutations resulting in abnormal calcium release from sarcoplasmic reticulum. Dantrolene, an inhibitor of sarcoplasmic Ca(2+) release, has been shown to rescue this abnormal Ca(2+) release in vitro. We assessed the antiarrhythmic efficacy of dantrolene in six patients carrying various RyR2 mutations causing CPVT. The patients underwent exercise stress test before and after dantrolene infusion. Dantrolene reduced the number of premature ventricular complexes (PVCs) on average by 74% (range 33-97) in four patients with N-terminal or central mutations in the cytosolic region of the RyR2 protein, while dantrolene had no effect in two patients with mutations in or near the transmembrane domain. Induced pluripotent stem cells (iPSCs) were generated from all the patients and differentiated into spontaneously beating cardiomyocytes (CMs). The antiarrhythmic effect of dantrolene was studied in CMs after adrenaline stimulation by Ca(2+) imaging. In iPSC derived CMs with RyR2 mutations in the N-terminal or central region, dantrolene suppressed the Ca(2+) cycling abnormalities in 80% (range 65-97) of cells while with mutations in or near the transmembrane domain only in 23 or 32% of cells. In conclusion, we demonstrate that dantrolene given intravenously shows antiarrhythmic effects in a portion of CPVT1 patients and that iPSC derived CM models replicate these individual drug responses. These findings illustrate the potential of iPSC models to individualize drug therapy of inherited diseases.Trial Registration: EudraCT Clinical Trial Registry 2012-005292-14.
MeSH term(s)	Adult ; Animals ; Anti-Arrhythmia Agents/administration & dosage ; Arrhythmias, Cardiac/drug therapy ; Arrhythmias, Cardiac/genetics ; Calcium/metabolism ; Cell Differentiation/drug effects ; Dantrolene/administration & dosage ; Epinephrine/metabolism ; Female ; Humans ; Induced Pluripotent Stem Cells ; Middle Aged ; Mutation ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/pathology ; Ryanodine Receptor Calcium Release Channel/genetics ; Tachycardia, Ventricular/drug therapy ; Tachycardia, Ventricular/genetics ; Tachycardia, Ventricular/pathology
Chemical Substances	Anti-Arrhythmia Agents ; Ryanodine Receptor Calcium Release Channel ; Dantrolene (F64QU97QCR) ; Calcium (SY7Q814VUP) ; Epinephrine (YKH834O4BH)
Language	English
Publishing date	2015-05-08
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0125366
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