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

Abstract

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.

Protective role of emodin in rats with post-myocardial infarction heart failure and influence on extracellular signal-regulated kinase pathway

“…Recently, mitochondrial production has been closely related to the regulation of mitochondrial functions, of which PGC-1 may be a key regulator. Especially, in the cardiovascular system, mitochondrial production regulated by the PGC-1 signaling pathway may be one of the main mechanisms for maintaining and repairing the mitochondrial function of cardiomyocytes and vascular endothelial cells, dominating in the onset and progression of cardiovascular diseases such as HF, myocardial hypertrophy and diabetes-induced cardiovascular complications [ 16 ].…”

Adding a “Notch” to Cardiovascular Disease Therapeutics: A MicroRNA-Based Approach

“…MiR-199a is upregulated in several models of HF ( Li Z. et al, 2017 ) but its role in the injured heart is still not completely understood. MiR-199a-3p inhibition through injection of adeno-associated virus (AAV)-anti-miR-199a reduces cardiac remodeling after MI ( Yan et al, 2021 ). In contrast, miR-199a overexpression stimulates cardiomyocytes de-differentiation and proliferation, determining cardiac regeneration in mice ( Eulalio et al, 2012 ) and pig model of MI ( Gabisonia et al, 2019 ).…”

MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure

“…Furthermore, anti-miR-199a attenuates cardiac hypertrophy and restores cardiac function in vivo through the PPARGC1A (PGC-1α)/ESRRA (ERRα) axis. The mechanism underlying restoration of mitochondrial structure and function in anti-miR-199atreated mice involves the downstream pathways of mitochondrial fatty acid oxidation and oxidative phosphorylation (107).…”