Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Arrhythmias, Cardiac / metabolism Calcium / metabolism Cardiomyopathy, Dilated / genetics Cells, Cultured Chromatin / chemistry Chromatin Assembly and Disassembly / genetics Haploinsufficiency / genetics Homeostasis Humans In Vitro Techniques Induced Pluripotent Stem Cells / pathology Lamin Type A / genetics Models, Biological Mutation Myocytes, Cardiac / metabolism Nonsense Mediated mRNA Decay Platelet-Derived Growth Factor / metabolism RNA, Messenger / analysis Receptor, Platelet-Derived Growth Factor beta / metabolism Signal Transduction Single-Cell Analysis

Journal

Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462

Informations de publication

Date de publication:
08 2019
Historique:
received: 13 07 2017
accepted: 19 06 2019
pubmed: 19 7 2019
medline: 18 12 2019
entrez: 19 7 2019
Statut: ppublish

Résumé

Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-β (PDGFRB) as a potential therapeutic target.

Identifiants

DOI: 10.1038/s41586-019-1406-x PMID: 31316208 PMC: PMC6779479
pubmed: 31316208
doi: 10.1038/s41586-019-1406-x
pii: 10.1038/s41586-019-1406-x
pmc: PMC6779479
mid: NIHMS1532384
doi:

Substances chimiques

Chromatin 0
LMNA protein, human 0
Lamin Type A 0
Platelet-Derived Growth Factor 0
RNA, Messenger 0
lamin C 0
Receptor, Platelet-Derived Growth Factor beta EC 2.7.10.1
Calcium SY7Q814VUP

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

335-340

Subventions

Organisme : NHGRI NIH HHS
ID : RM1 HG007735
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL113006
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL133473
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130020
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141851
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL133473
Pays : United States
Organisme : NHLBI NIH HHS
ID : R24 HL117756
Pays : United States
Organisme : NHGRI NIH HHS
ID : P50 HG007735
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL104002
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL094274
Pays : United States
Organisme : NHLBI NIH HHS
ID : F32 HL139045
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132875
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139679
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128170
Pays : United States

Commentaires et corrections

Type : CommentIn

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Auteurs

Jaecheol Lee (J)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. jaecheol@skku.edu.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA. jaecheol@skku.edu.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. jaecheol@skku.edu.
School of Pharmacy, Sungkyunkwan University, Suwon, South Korea. jaecheol@skku.edu.

Vittavat Termglinchan (V)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Sebastian Diecke (S)

Berlin Institute of Health, Berlin, Germany.
Max Delbrueck Center, Berlin, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.

Ilanit Itzhaki (I)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Chi Keung Lam (CK)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Priyanka Garg (P)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Edward Lau (E)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Matthew Greenhaw (M)

Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Timon Seeger (T)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Haodi Wu (H)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Joe Z Zhang (JZ)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Xingqi Chen (X)

Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.

Isaac Perea Gil (IP)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Mohamed Ameen (M)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Karim Sallam (K)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

June-Wha Rhee (JW)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Jared M Churko (JM)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Rinkal Chaudhary (R)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Tony Chour (T)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.

Paul J Wang (PJ)

Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.

Michael P Snyder (MP)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Howard Y Chang (HY)

Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.

Ioannis Karakikes (I)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. ioannis1@stanford.edu.
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA. ioannis1@stanford.edu.

Joseph C Wu (JC)

Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. joewu@stanford.edu.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA. joewu@stanford.edu.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. joewu@stanford.edu.

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Classifications MeSH

questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Troubles du rythme cardiaque › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Facteurs biologiques › Facteurs de la coagulation sanguine › Calcium › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Laminopathies › Cardiomyopathie dilatée › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Cellules › Cellules cultivées › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Assemblage et désassemblage de la chromatine › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Phénomènes physiologiques › Homéostasie › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines associées à la matrice nucléaire › Lamines › Lamine A › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Cellules › Cellules musculaires › Myocytes cardiaques › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Dégradation des ARNm non-sens › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Facteur de croissance dérivé des plaquettes › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN messager › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs aux facteurs de croissance dérivés des plaquettes › Récepteur au PDGF bêta › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Activation of PDGF pathway links LMNA mutation...
questionsmedicales.fr › Techniques d'investigation › Techniques cytologiques › Analyse sur cellule unique › Activation of PDGF pathway links LMNA mutation...