Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy by targeting PGC-1alpha

• Main Authors: Hualin Yan, Hong Wang, Xiaoxia Zhu, Jianbo Huang, Yifei Li, Kaiyu Zhou, Yimin Hua, Feng Yan, Da-Zhi Wang, Yan Luo
• Format: Article
• Language: English
• Published: Elsevier 2021-03-01
• Series: Molecular Therapy: Nucleic Acids
• Subjects: adeno-associated virus; microRNA-199a; cardiac hypertrophy; heart failure; PGC1-alpha
• Online Access: http://www.sciencedirect.com/science/article/pii/S2162253120303632
• ISSN: 2162-2531

MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies have shown that miR-199a is upregulated in pressure-overload cardiac hypertrophy and that inhibition of miR-199a attenuates cardiac hypertrophy in vitro. However, the therapeutic role of anti-miR-199a treatment in the cardiac hypertrophy in vivo model is less known. Here, we show an efficient and useful method to treat mouse cardiac hypertrophy and restore cardiac function through injection of adeno-associated virus (AAV)-mediated anti-miR-199a tough decoys (TuDs). RNA-seq transcriptome analysis indicated that genes related to cytoplasmic translation and mitochondrial respiratory chain complex assembly were upregulated in anti-miR-199a-treated recovered hearts. We further validated that PGC-1α is the direct target of miR-199a involved in the therapeutic effect and the regulation of the PGC-1α/ERRα axis and that the downstream pathway of mitochondrial fatty acid oxidation and oxidative phosphorylation constitute the underlying mechanism of the restored mitochondrial structure and function in our anti-miR-199a-treated mice. Our study highlights the important regulatory role of miR-199a in cardiac hypertrophy and the value of the AAV-mediated miRNA delivery system.