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. Wang; Michael P. Snyder; Howard Y. Chang; Ioannis Karakikes; Joseph C. Wu

doi:10.1038/s41586-019-1406-x

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 journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	335-340
Number of pages	6
Journal	Nature
Volume	572
Issue number	7769
DOIs	https://doi.org/10.1038/s41586-019-1406-x
State	Published - Aug 15 2019

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Lee, J., Termglinchan, V., Diecke, S., Itzhaki, I., Lam, C. K., Garg, P., Lau, E., Greenhaw, M., Seeger, T., Wu, H., Zhang, J. Z., Chen, X., Gil, I. P., Ameen, M., Sallam, K., Rhee, J. W., Churko, J. M., Chaudhary, R., Chour, T., ... 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 journal › Article › peer-review

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, 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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title = "Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy",

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.",

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

note = "Funding Information: Acknowledgements We thank members of the laboratory of D. M. Bers for providing the pRYR2 antibody, and S. A. Yi, K. H. Nam, G. A. Akgun, C. Chen and S. Zhang for their contribution. This research is supported by AHA 17MERIT33610009, NIH R01 HL128170, R01 HL113006, R01 HL130020, R01 HL132875, R01 HL141851, Leducq Foundation 18CVD05 (J.C.W.); R01 HL139679, R00 HL104002, AHA 17IRG33410532 (I.K.); Prince Mahidol Award Foundation (V.T.); NIH K99 HL133473 (H.W.); the German Research Foundation (T.S.); National Research Foundation of Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41586-019-1406-x",

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T1 - Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

AU - Lee, Jaecheol

AU - Termglinchan, Vittavat

AU - Diecke, Sebastian

AU - Itzhaki, Ilanit

AU - Lam, Chi Keung

AU - Garg, Priyanka

AU - Lau, Edward

AU - Greenhaw, Matthew

AU - Seeger, Timon

AU - Wu, Haodi

AU - Zhang, Joe Z.

AU - Chen, Xingqi

AU - Gil, Isaac Perea

AU - Ameen, Mohamed

AU - Sallam, Karim

AU - Rhee, June Wha

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.

N1 - Funding Information: Acknowledgements We thank members of the laboratory of D. M. Bers for providing the pRYR2 antibody, and S. A. Yi, K. H. Nam, G. A. Akgun, C. Chen and S. Zhang for their contribution. This research is supported by AHA 17MERIT33610009, NIH R01 HL128170, R01 HL113006, R01 HL130020, R01 HL132875, R01 HL141851, Leducq Foundation 18CVD05 (J.C.W.); R01 HL139679, R00 HL104002, AHA 17IRG33410532 (I.K.); Prince Mahidol Award Foundation (V.T.); NIH K99 HL133473 (H.W.); the German Research Foundation (T.S.); National Research Foundation of Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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.

AB - 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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SN - 0028-0836

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Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

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