This study sought to identify new miRNA candidates that regulate cardiac autophagy and aging.
We exploited a high-throughput, fluorescence-activated cell sorting-based green fluorescent protein–LC3 detection method to measure the autophagic flux in cardiomyocytes after transfection of a precursor miRNA library consisting of 380 miRNAs. This was followed by a series of molecular and in vivo studies.
Together with additional expression screenings, we identified miR-22 as an abundant and strong inhibitor of the cardiac autophagy process. Cardiac miR-22 expression levels increased during aging of mice as well as in aging neonatal cardiomyocytes in vitro by a P53-dependent mechanism. Inhibition of miR-22 in aging cardiomyocytes in vitro activated autophagy and inhibited cellular hypertrophy. Pharmacological inhibition of miR-22 post-MI in older mice activated cardiac autophagy, prevented post-infarction remodeling, and improved cardiac function compared with control subjects. Interestingly, similar effects were less pronounced in younger mice with significantly lower cardiac miR-22 expression levels. In addition, circulating levels of miR-22 in 154 patients with systolic HF were highly associated with early mortality.
We concluded that miR-22 is an important regulator of cardiac autophagy and a potential therapeutic target, especially in the older myocardium. Finally, circulating miR-22 provides prognostic information for HF patients, highlighting miR-22 as a promising therapeutic and biomarker candidate for cardiovascular disorders.