2. Academic Validation
  3. Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model

Lamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model

  • Nat Commun. 2024 Aug 14;15(1):7000. doi: 10.1038/s41467-024-51318-5.
Hangyuan Qiu 1 2 3,  Yaxun Sun 1 2,  Xiaochen Wang 4 5,  Tingyu Gong 4 5,  Jun Su 4 5,  Jiaxi Shen 4 5,  Jingjun Zhou 4 5,  Jiafeng Xia 6,  Hao Wang 7,  Xiangfu Meng 8,  Guosheng Fu 1 2,  Donghui Zhang 8,  Chenyang Jiang 9 10,  Ping Liang 11 12
Affiliations

Affiliations

  • 1 Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
  • 3 Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 4 Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Institute of Translational Medicine, Zhejiang University, Hangzhou, China.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Prenatal Diagnosis Center, Hangzhou Women's Hospital, Hangzhou, China.
  • 8 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China.
  • 9 Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. cyjiang@zju.edu.cn.
  • 10 Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China. cyjiang@zju.edu.cn.
  • 11 Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. pingliang@zju.edu.cn.
  • 12 Institute of Translational Medicine, Zhejiang University, Hangzhou, China. pingliang@zju.edu.cn.
PMID: 39143095 DOI: 10.1038/s41467-024-51318-5
Abstract

Mutations in the nuclear envelope (NE) protein lamin A/C (encoded by LMNA), cause a severe form of dilated cardiomyopathy (DCM) with early-onset life-threatening arrhythmias. However, molecular mechanisms underlying increased arrhythmogenesis in LMNA-related DCM (LMNA-DCM) remain largely unknown. Here we show that a frameshift mutation in LMNA causes abnormal CA2+ handling, arrhythmias and disformed NE in LMNA-DCM patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). Mechanistically, lamin A interacts with Sirtuin 1 (SIRT1) where mutant lamin A/C accelerates degradation of SIRT1, leading to mitochondrial dysfunction and oxidative stress. Elevated Reactive Oxygen Species (ROS) then activates the CA2+/calmodulin-dependent protein kinase II (CaMKII)-ryanodine receptor 2 (RYR2) pathway and aggravates the accumulation of SUN1 in mutant iPSC-CMs, contributing to arrhythmias and NE deformation, respectively. Taken together, the lamin A/C deficiency-mediated ROS disorder is revealed as central to LMNA-DCM development. Manipulation of impaired SIRT1 activity and excessive oxidative stress is a potential future therapeutic strategy for LMNA-DCM.

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