Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

Jaecheol Lee, Vittavat Termglinchan, Sebastian Diecke, Ilanit Itzhaki, Chi Keung Lam, Priyanka Garg, Edward Lau, Matthew Greenhaw, Timon Seeger, Haodi Wu, Joe Z. Zhang, Xingqi Chen, Isaac Perea Gil, Mohamed Ameen, Karim Sallam, June Wha Rhee, Jared M. Churko, Rinkal Chaudhary, Tony Chour, Paul J. WangMichael P. Snyder, Howard Y. Chang, Ioannis Karakikes, Joseph C. Wu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)335-340
Number of pages6
JournalNature
Volume572
Issue number7769
DOIs
StatePublished - Aug 15 2019
Externally publishedYes

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Lamin Type A
Induced Pluripotent Stem Cells
Platelet-Derived Growth Factor
Dilated Cardiomyopathy
Cardiac Myocytes
Mutation
Cardiac Arrhythmias
Platelet-Derived Growth Factor beta Receptor
Platelet-Derived Growth Factor Receptors
Cardiomyopathies
Homeostasis
Pharmacology
Calcium
Phenotype
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • General

Cite this

Lee, J., Termglinchan, V., Diecke, S., Itzhaki, I., Lam, C. K., Garg, P., ... Wu, J. C. (2019). Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature, 572(7769), 335-340. https://doi.org/10.1038/s41586-019-1406-x

Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. / Lee, Jaecheol; Termglinchan, Vittavat; Diecke, Sebastian; Itzhaki, Ilanit; Lam, Chi Keung; Garg, Priyanka; Lau, Edward; Greenhaw, Matthew; Seeger, Timon; Wu, Haodi; Zhang, Joe Z.; Chen, Xingqi; Gil, Isaac Perea; Ameen, Mohamed; Sallam, Karim; Rhee, June Wha; Churko, Jared M.; Chaudhary, Rinkal; Chour, Tony; Wang, Paul J.; Snyder, Michael P.; Chang, Howard Y.; Karakikes, Ioannis; Wu, Joseph C.

In: Nature, Vol. 572, No. 7769, 15.08.2019, p. 335-340.

Research output: Contribution to journalArticle

Lee, J, Termglinchan, V, Diecke, S, Itzhaki, I, Lam, CK, Garg, P, Lau, E, Greenhaw, M, Seeger, T, Wu, H, Zhang, JZ, Chen, X, Gil, IP, Ameen, M, Sallam, K, Rhee, JW, Churko, JM, Chaudhary, R, Chour, T, Wang, PJ, Snyder, MP, Chang, HY, Karakikes, I & Wu, JC 2019, 'Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy', Nature, vol. 572, no. 7769, pp. 335-340. https://doi.org/10.1038/s41586-019-1406-x
Lee J, Termglinchan V, Diecke S, Itzhaki I, Lam CK, Garg P et al. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature. 2019 Aug 15;572(7769):335-340. https://doi.org/10.1038/s41586-019-1406-x
Lee, Jaecheol ; Termglinchan, Vittavat ; Diecke, Sebastian ; Itzhaki, Ilanit ; Lam, Chi Keung ; Garg, Priyanka ; Lau, Edward ; Greenhaw, Matthew ; Seeger, Timon ; Wu, Haodi ; Zhang, Joe Z. ; Chen, Xingqi ; Gil, Isaac Perea ; Ameen, Mohamed ; Sallam, Karim ; Rhee, June Wha ; Churko, Jared M. ; Chaudhary, Rinkal ; Chour, Tony ; Wang, Paul J. ; Snyder, Michael P. ; Chang, Howard Y. ; Karakikes, Ioannis ; Wu, Joseph C. / Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. In: Nature. 2019 ; Vol. 572, No. 7769. pp. 335-340.
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abstract = "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.",
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AU - Diecke, Sebastian

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AU - Lam, Chi Keung

AU - Garg, Priyanka

AU - Lau, Edward

AU - Greenhaw, Matthew

AU - Seeger, Timon

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AU - Zhang, Joe Z.

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AU - Ameen, Mohamed

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AU - Churko, Jared M.

AU - Chaudhary, Rinkal

AU - Chour, Tony

AU - Wang, Paul J.

AU - Snyder, Michael P.

AU - Chang, Howard Y.

AU - Karakikes, Ioannis

AU - Wu, Joseph C.

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