Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for Lmna-Associated Cardiac Defects in Mice

The truncating mutations of <i>LMNA</i> are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic <i>Lmna</i> truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, <i>Lmna</i> regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for <i>Lmna</i>-associated cardiac defects.

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Publication Details

Journal
JACC Basic to Translational Science
Published
2024-08-23
DOI
https://doi.org/10.1016/j.jacbts.2024.06.004
Citations
6
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
1.40
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article

Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for Lmna-Associated Cardiac Defects in Mice

Luzi Yang, Dongyu Zhao, Blake D. Jardin, Congting Guo et al.
6 citations
JACC Basic to Translational Science
Congenital heart defects research
1.40
article

Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for Lmna-Associated Cardiac Defects in Mice

Luzi Yang, Dongyu Zhao, Blake D. Jardin, Congting Guo, William T. Pu, Erdan Dong, Yuxuan Guo, Junsen Lin, Zhan Chen, Xiaomin Hu, Chenyang Wu, Mingming Zhao, Yueyang Zhang, Shuyang Zhang, Yueshen Sun
article en
6 citations

Abstract

The truncating mutations of <i>LMNA</i> are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic <i>Lmna</i> truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, <i>Lmna</i> regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for <i>Lmna</i>-associated cardiac defects.

JACC Basic to Translational ScienceVol. 9(11)
Qingdao University (CN), Boston Children's Hospital (US), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), National Health and Family Planning Commission (CN), Peking Union Medical College Hospital (CN), Affiliated Hospital of Qingdao University (CN), Qingdao Municipal Hospital (CN), Peking University Third Hospital (CN)
Zero hunger
Openalex Percentile: Top 19%
Congenital heart defects research
1.40
DOIOpen Access PDFOpenAlex
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