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最终导致心力衰竭中的重要作用。在这里，我们的目标是通过 AAV 介导的靶向 NFATc1-c4 的基于 RNA 的诱饵寡核苷酸 (dON) 的心脏表达，中和 NFAT 转录因子家族的四个成员，作为心肌肥大转变为心力衰竭的治疗策略。荧光原位杂交证明，AAV 介导的 dON 表达显着降低了体外内皮素-1 诱导的心肌细胞肥大，并导致这些 dON 在成年小鼠心脏中有效表达。在诱导主动脉横缩之前和之后，心肌细胞特异性 dON 表达可以保护小鼠免于发生心脏肥大、心脏重塑和心力衰竭。因此，AAV 的单一全身给药能够实现 dON 的细胞特异性表达，从而选择性中和给定的转录因子，这可能代表了一种新颖而强大的治疗方法。