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

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS JACC: Basic to Translational Science Pub Date : 2024-11-01 DOI:10.1016/j.jacbts.2024.06.004

Yueshen Sun MB , Congting Guo BS , Zhan Chen BS , Junsen Lin BS , Luzi Yang MM , Yueyang Zhang BS , Chenyang Wu BS , Dongyu Zhao PhD , Blake Jardin MS , William T. Pu MD , Mingming Zhao PhD , Erdan Dong MD , Xiaomin Hu PhD , Shuyang Zhang MD , Yuxuan Guo PhD

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Abstract

The truncating mutations of LMNA are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic Lmna 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, Lmna regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for Lmna-associated cardiac defects.

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非细胞自主性心肌细胞调控使小鼠 Lmna 相关心脏缺陷的基因补充疗法变得复杂

LMNA 截断突变是心肌病的主要病因。在这里，我们研究了携带种系、心肌细胞特异性或遗传镶嵌Lmna截短突变的3种小鼠模型。种系突变体表现出心脏成熟缺陷，而心肌细胞特异性突变则引发病理性肥大。在基因镶嵌分析中，没有观察到形态学缺陷。应用三种腺相关病毒（AAV）载体，以普遍存在、心肌细胞特异性或心肌细胞排除的方式加回了lamin-A。令人震惊的是，只有无处不在和排除心肌细胞的 AAV 载体能缓解心脏缺陷。因此，Lmna 通过非细胞自主机制调节心脏形态和功能。非心肌细胞是 AAV lamin-A 治疗 Lmna 相关心脏缺陷的关键靶点。

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.

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