Our aims were to investigate the pathogenesis of diabetic cardiomyopathy (DCM) and to explore the protective effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) on DCM. Methods: After 12 weeks of treatment with exenatide-loaded microspheres, a long-acting GLP-1RA, in DCM mice, cardiac structure and function were evaluated by plasma B-type natriuretic peptide (BNP), echocardiography, H&E, oil red and Sirius staining. The expression of glucagon-like peptide-1 receptor in mouse heart tissue was determined by immunofluorescence staining. The label-free proteomic analysis of cardiac proteins was conducted among control, DCM and DM+GLP-1RA groups. Then, quantitative real-time PCR, Western blotting and dual-luciferase reporter assay were performed to verify the regulation of target protein by the upstream microRNA (miRNA). Results: GLP-1RA treatment obviously improved serum BNP, myocardial fibrosis, lipid deposition of the myocardium and echocardiography parameters in DCM mice. Sarcolemmal membrane-associated protein (SLMAP) was one of 61 differentially expressed cardiac proteins found in three groups by proteomic analysis. Up-regulation of microRNA-29b-3p (miR-29b-3p) and down-regulation of SLMAP were found in the ventricular myocardium of GLP-1RA-treated DCM mice. SLMAP was a target of miR-29b-3p, while GLP-1RA regulated SLMAP expression through miR-29b-3p. Furthermore, inhibition of glucagon-like peptide-1 receptor (GLP-1R) in cardiomyocytes reversed the effects of GLP-1RA on miR-29b/SLMAP. Conclusion: SLMAP may play roles in the pathogenesis of DCM and may be a target of GLP-1RA in protecting against DCM. After binding to myocardial GLP-1R, GLP-1RA can regulate the expression of myocardial SLMAP through miR-29b-3p.

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Previous studies have found microRNA‐1 (miR‐1) and hyperpolarization‐activated cyclic nucleotide‐gated channel 2 (HCN2) may be involved in the pathogenesis of thyroid hormone (TH) induced cardiac hypertrophy. However, little is known about the role of miR‐1 and HCN2 in thyroid stimulation hormone (TSH)‐induced cardiac dysfunction. In order to investigate the molecular mechanisms of TSH induced cardiac dysfunction and the role of miR‐1/HCN2 in that process, we evaluated the expression of miR‐1a/HCN2 in the ventricular myocardium of hypothyroid mice and in TSH‐stimulated H9c2 cardiomyocytes. Our data revealed that hypothyroidism mice had smaller hearts, ventricular muscle atrophy, and cardiac contractile dysfunction compared with euthyroid controls. The upregulation of miR‐1a and downregulation of HCN2 were found in ventricular myocardium of hypothyroid mice and TSH‐stimulated H9c2 cardiomyocytes, indicating that miR‐1a and HCN2 may be involved in TSH‐induced cardiac dysfunction. We also found that the regulation of miR‐1a and HCN2 expression and HCN2 channel activity by TSH requires TSHR, while the regulation of HCN2 expression and HCN2 channel function by TSH requires miR‐1a. Thus, our data revealed the potential mechanism of TSH‐induced cardiac dysfunction and might shed new light on the pathological role of miR‐1a/HCN2 in hypothyroid heart disease.

Objective Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been extensively studied, the role of its underlying pathogenesis remains unclear, and there is currently no approved therapeutic strategy for NAFLD. The purpose of this study was to observe the beneficial effects of Semaglutide on NAFLD in vivo and in vitro, as well as its potential molecular mechanisms. Methods Semaglutide was used to treat type 2 diabetes mellitus (T2DM) combined with NAFLD mice for 12 weeks. Hepatic function and structure were evaluated by liver function, blood lipids, liver lipids, H&E staining, oil red staining and Sirius staining. The expression of α/β hydrolase domain-6 (ABHD6) was measured by qPCR and Western blotting in vivo and in vitro. Then, dual-luciferase reporter assay was performed to verify the regulation of the upstream miR-5120 on ABHD6. Results Our data revealed that Semaglutide administration significantly improved liver function and hepatic steatosis in T2DM combined with NAFLD mice. Furthermore, compared with controls, up-regulation of ABHD6 and down-regulation of miR-5120 were found in the liver of T2DM+NAFLD mice and HG+FFA-stimulated Hepa 1–6 hepatocytes. Interestingly, after Semaglutide intervention, ABHD6 expression was significantly decreased in the liver of T2DM+NAFLD mice and in HG+FFA-stimulated Hepa 1–6 hepatocytes, while miR-5120 expression was increased. We also found that miR-5120 could regulate the expression of ABHD6 in hepatocytes, while Semaglutide could modulate the expression of ABHD6 through miR-5120. In addition, GLP-1R was widely expressed in mouse liver tissues and Hepa 1–6 cells. Semaglutide could regulate miR-5120/ABHD6 expression through GLP-1R. Conclusion Our data revealed the underlying mechanism by which Semaglutide improves hepatic steatosis in T2DM+NAFLD, and might shed new light on the pathological role of miR-5120/ABHD6 in the pathogenesis of T2DM+NAFLD.