Research Paper Volume 4, Issue 11 pp 803—822
Modeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells
- 1 Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong SAR, China
- 2 Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China
- 3 Institute of Medical Biology, A*STAR Institute of Medical Biology, Singapore
Received: August 1, 2012 Accepted: November 28, 2012 Published: December 3, 2012
https://doi.org/10.18632/aging.100503How to Cite
Abstract
AIMS
We identified an autosomal dominant non-sense mutation (R225X) in exon 4 of the lamin A/C (LMNA) gene in a Chinese family spanning 3 generations with familial dilated cardiomyopathy (DCM). In present study, we aim to generate induced pluripotent stem cells derived cardiomyocytes (iPSC-CMs) from an affected patient with R225X and another patient bearing LMNA frame-shift mutation for drug screening.
METHODS and RESULTS
Higher prevalence of nuclear bleb formation and micronucleation was present in LMNAR225X/WT and LMNAFramshift/WT iPSC-CMs. Under field electrical stimulation, percentage of LMNA-mutated iPSC-CMs exhibiting nuclear senescence and cellular apoptosis markedly increased. shRNA knockdown of LMNA replicated those phenotypes of the mutated LMNA field electrical stress. Pharmacological blockade of ERK1/2 pathway with MEK1/2 inhibitors, U0126 and selumetinib (AZD6244) significantly attenuated the pro-apoptotic effects of field electric stimulation on the mutated LMNA iPSC-CMs.
CONCLUSION
LMNA-related DCM was modeled in-vitro using patient-specific iPSC-CMs. Our results demonstrated that haploinsufficiency due to R225X LMNA non-sense mutation was associated with accelerated nuclear senescence and apoptosis of iPSC- CMs under electrical stimulation, which can be significantly attenuated by therapeutic blockade of stress-related ERK1/2 pathway.