腺相关病毒介导的 NFAT 诱饵寡核苷酸表达可防止心肌肥厚和心力衰竭。
AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure.
机构信息
Department of Internal Medicine III, University Hospital Schleswig-Holstein and University of Kiel , Arnold-Heller-Str. 3 , Kiel, Germany.
Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.
出版信息
Basic Res Cardiol. 2021 Jun 4;116(1):38. doi: 10.1007/s00395-021-00880-w.
Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.
先前的研究强调了活化 T 细胞核因子（NFAT）在高血压引起的心肌肥厚中的重要作用，而心肌肥厚最终会导致心力衰竭。在这里，我们旨在通过 AAV 介导的心脏表达靶向 NFATc1-c4 的 RNA 诱饵寡核苷酸（dON）来中和 NFAT 家族的四个转录因子成员，以此作为一种治疗策略，用于治疗从心肌肥厚向心力衰竭转变。AAV 介导的 dON 表达显著抑制了内皮素-1诱导的体外心肌细胞肥大，并通过荧光原位杂交证明了这些 dON 在成年小鼠心脏中的有效表达。在诱导主动脉缩窄之前和之后，心肌细胞特异性 dON 表达均可保护小鼠免于发生心肌肥厚、心脏重构和心力衰竭。通过 AAV 进行单一的系统性给药，能够实现 dON 的细胞特异性表达，从而选择性地中和特定的转录因子，这可能代表一种新颖而强大的治疗方法。
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