MicroRNA‑138‑5p drives the progression of heart failure via inhibiting sirtuin 1 signaling

Abstract

The present study aimed to investigate the regulatory effects of microRNA-138-5p (miR-138-5p) and sirtuin 1 (SIRT1) on the progression of heart failure (HF). The binding association between miR-138-5p and SIRT1 was assessed by the dual-luciferase reporter assay. By conducting reverse transcription-quantitative polymerase chain reaction and Western blotting, relative levels of SIRT1 and p53 regulated by miR-138-5p were detected. In vitro HF models were generated by hydrogen peroxide (H 2 O 2 ) induction in AC-16 and human cardiomyocyte (HCM) cells, followed by detection of the regulatory effects of SIRT1 on cell apoptosis and p53 expression. MiR-138-5p was negatively correlated with the SIRT1 level in cardiomyocytes. By recognizing and specifically targeting SIRT1 3′-untranslated region (3′-UTR), miR-138-5p decreased the translational level of SIRT1 and inhibited its enzyme activity, thereby decreasing the deacetylation level of p53. Through downregulating SIRT1 and activating p53 signaling, miR-138-5p induced apoptosis in H 2 O 2 -induced AC-16 and HCM cells. By contrast, knockdown of miR-138-5p in the in vitro HF models significantly protected the cardiomyocytes. SIRT1 contributed toward alleviate HF by inhibiting cardiomyocyte apoptosis via enhancing the deacetylation level of p53. MiR-138-5p decreases the enzyme activity of SIRT1 by specifically targeting its 3′-UTR and activates p53 signaling, followed by triggering cardiomyocyte apoptosis during the process of HF. It is considered that miR-138-5p and SIRT1 may be potential diagnostic biomarkers and therapeutic targets for HF.

The sirtuin family in health and disease

“…528,529 Heart failure is closely related to some biological processes, such as oxidative stress and cell apoptosis. 530,531 SIRT1 might attenuate oxidative stress and protect cells from oxidative damage and apoptosis through several mechanisms. 531 For example, levels of MnSOD, thiore-doxin1, and Bcl-xL (an anti-apoptotic molecule) are significantly decreased in cardiomyocytes from individuals with advanced heart failure.…”

“… 530 , 531 SIRT1 might attenuate oxidative stress and protect cells from oxidative damage and apoptosis through several mechanisms. 531 For example, levels of MnSOD, thioredoxin1, and Bcl-xL (an anti-apoptotic molecule) are significantly decreased in cardiomyocytes from individuals with advanced heart failure. 528 The low expression of SIRT1 might downregulate antioxidants and upregulate pro-apoptotic molecules by increasing p53 acetylation and decreasing FoxO1 translocation in the nucleus.…”

MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure

“…MiR-138-5p can decrease SIRT1 expression in H 2 O 2 -induced AC-16 and HCM cells by activating P53 signaling. By contrast, in vitro knockdown of miR-138-5p has a clear protective effect on cardiomyocytes in HF models (118). In summary, miR-138-5p inhibits SIRT1 enzyme activity by activating P53 signaling, resulting in deterioration of HF (118).…”

Role of Posttranslational Modifications of Proteins in Cardiovascular Disease

“…This site may be a new strategy for the treatment of heart failure [ 89 ]. SIRT1 alleviates HF by increasing the deacetylation level of p53 and inhibiting myocardial cell apoptosis [ 90 ]. In mitochondria, both fatty acid oxidation and complex I deficiency increase protein acetylation, exacerbating cardiac dysfunction and heart failure [ 91 ].…”