MiR-669a-5p improves cardiomyocyte energy metabolism via AMPK/PGC1α signaling pathway in mice with heart failure

Abstract

Objective To investigate the change in expression of microRNA-669a-5p (miR-669a-5p) in mice with heart failure (HF) induced by transverse aortic constriction (TAC) and to further explore the role and possible mechanism of miR-669a-5p in HF mice. Methods Twenty-four mice were randomly divided into the sham surgery group (Sham group, n=8) and the surgery group (n=16, TAC induced HF model). In the 4th week after TAC surgery, the mice from the surgery group was randomized into the model group (TAC group, n=8) and miR-669a-5p agomir group (Agomir group, n=8). Normal saline, agomir negative control and agomir reagent were respectively injected via tail vein into the corresponding groups, twice a week for 4 weeks. In the 8th week after TAC, the cardiac function of each group was measured by echocardiography. HE, Sirius red and WGA staining were used to observe the pathological changes in the myocardium tissues. The expression of miR-669a-5p and oxidative phosphorylation related genes (ND1, ND2, NDUFA4 and ATP5O) were detected by RT-qPCR. The ATP content of myocardial tissues in each group was measured by ATP assay kit. The protein levels of AMPK, p-AMPK and PGC-1α were detected by Western blotting. Results The expression of miR-669a-5p was significantly decreased in the TAC group compared with the Sham group (P < 0.05). Compared with those in the TAC group, echocardiography showed that the Agomir group significantly improved cardiac function (P < 0.05), as well as histopathological analysis suggested that the Agomir group significantly improved cardiac remodeling (P < 0.05). The ATP levels in the Agomir group were significantly higher than that in the TAC group (P < 0.05), and the mRNA levels of ND1, ND2, NDUFA4 and ATP5O were dramatically higher (P < 0.05). Western blotting showed that the protein levels of p-AMPK/AMPK and PGC1α were significantly up-regulated in the Agomir group compared with the TAC group (P < 0.05). Conclusion MiR-669a-5p significantly improves cardiac function and cardiac remodeling in mice with TAC-induced HF, and the mechanism may be associated with the up-regulation of AMPK/PGC1α signaling pathway and further improvement of myocardial energy metabolism in mice.

Keywords

• mir-669a-5p
• heart failure
• energy metabolism
• oxidative phosphorylation
• ampk/pgc1α