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Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Nature. 2019 Aug;572(7769):335-340. Epub 2019 Jul 17
Jaecheol Lee 1 , Vittavat Termglinchan 2 , Sebastian Diecke 3 , Ilanit Itzhaki 2 , Chi Keung Lam 2 , Priyanka Garg 2 , Edward Lau 2 , Matthew Greenhaw 4 , Timon Seeger 2 , Haodi Wu 2 , Joe Z Zhang 2 , Xingqi Chen 5 , Isaac Perea Gil 4 , Mohamed Ameen 2 , Karim Sallam 2 , June-Wha Rhee 2 , Jared M Churko 2 , Rinkal Chaudhary 2 , Tony Chour 2 , Paul J Wang 6 , Michael P Snyder 7 , Howard Y Chang 8 , Ioannis Karakikes 9 , Joseph C Wu 10
Jaecheol Lee 1 , Vittavat Termglinchan 2 , Sebastian Diecke 3 , Ilanit Itzhaki 2 , Chi Keung Lam 2 , Priyanka Garg 2 , Edward Lau 2 , Matthew Greenhaw 4 , Timon Seeger 2 , Haodi Wu 2 , Joe Z Zhang 2 , Xingqi Chen 5 , Isaac Perea Gil 4 , Mohamed Ameen 2 , Karim Sallam 2 , June-Wha Rhee 2 , Jared M Churko 2 , Rinkal Chaudhary 2 , Tony Chour 2 , Paul J Wang 6 , Michael P Snyder 7 , Howard Y Chang 8 , Ioannis Karakikes 9 , Joseph C Wu 10
+ et al

[No authors listed]

Author information
  • 1 School of Pharmacy, Sungkyunkwan University, Suwon, South Korea. jaecheol@skku.edu.
  • 2 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
  • 3 DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
  • 4 Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
  • 6 Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
  • 7 Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 8 Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
  • 9 Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA. ioannis1@stanford.edu.
  • 10 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. joewu@stanford.edu.

摘要

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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