miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation

Abstract

Basal autophagy is tightly regulated by transcriptional and epigenetic factors to maintain cellular homeostasis. Dysregulation of cardiac autophagy is associated with heart diseases, including cardiac hypertrophy, but the mechanism governing cardiac autophagy is rarely identified. To analyze the in vivo function of miR-199a in cardiac autophagy and cardiac hypertrophy, we generated cardiac-specific miR-199a transgenic mice and showed that overexpression of miR-199a was sufficient to inhibit cardiomyocyte autophagy and induce cardiac hypertrophy in vivo. miR-199a impaired cardiomyocyte autophagy in a cell-autonomous manner by targeting glycogen synthase kinase 3β (GSK3β)/mammalian target of rapamycin (mTOR) complex signaling. Overexpression of autophagy related gene 5 (Atg5) attenuated the hypertrophic effects of miR-199a overexpression on cardiomyocytes, and activation of autophagy using rapamycin was sufficient to restore cardiac autophagy and decrease cardiac hypertrophy in miR-199a transgenic mice. These results reveal a novel role of miR-199a as a key regulator of cardiac autophagy, suggesting that targeting miRNAs controlling autophagy as a potential therapeutic strategy for cardiac disease.

Therapeutic targeting of autophagy in myocardial infarction and heart failure

“…Consistently, the hypertrophic effects of miR-199a could be reversed by overexpression of Atg5 or rapamycin treatment [119]. Similar results have been obtained in studies focusing on miR-30-Ang II [120], miR-34a-Ang II [121], and miR-451-tuberous sclerosis complex 1 [122] autophagy-mediated cardiomyocyte hypertrophy.…”

MicroRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells

“…In addition, the expression level of miR-199a-5p was significantly increased in gastric cancer tissues compared with paired normal tissues, and higher miR-199a-5p level was associated with increased lymph node metastasis and higher tumor-node-metastasis stage, suggesting that miR-199a-5p may act as an oncogene in gastric cancer (26). Recently, miR-199a-5p has been reported to exhibit inhibitory effects on autophagy (27). For instance, Lee et al observed that protoporphyrin IX, a photocatalyzer, could increase the expression of miR-199a-5p, which further inhibited E2F transcription factor 3 and sensitized mesenchymal tumor cells to chemotherapy drugs (28).…”

The role of autophagy in angiotensin II-induced pathological cardiac hypertrophy

“…Several miRNAs that induce pathological hypertrophy and heart failure have been identified, such as miR-195, miR-21, miR23a and miR-208a, whereas miR-133 and miR-1 negatively regulate cardiac hypertrophy (Yang et al 2011). Many studies have shown that miRNAs regulate both cardiac hypertrophy and cardiomyocyte autophagy, for example, miR-212/132 and miR-199a; induce cardiac hypertrophy; and attenuate the autophagic response in cardiomyocytes (Ucar et al 2012, Li et al 2015a. Ang II-induced cardiomyocyte hypertrophy in terms of cell area of cardiomyocytes and expression of the cardiomyocyte hypertrophy markers atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) mRNA; moreover, the level of ATG9A protein and mRNA expression was upregulated.…”