The GLP-1 Analogue Liraglutide Protects Cardiomyocytes from High Glucose-induced Apoptosis by Activating the Epac-1/Akt Pathway

 

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Abstract

Background: Cardiomyocyte apoptosis is closely related to cardiac dysfunction in diabetic patients. Although GLP-1 analogs are used as anti-diabetic drugs, their effects on cardiomyocytes remain unclear. The aim of this study was to assess the effects of the GLP-1 analog liraglutide on high glucose-induced cardiomyocyte apoptosis.

Methods: Wistar rats were divided into normal (N), diabetes mellitus (DM), and liraglutide (LIR) groups. H9c2 cardiomyocytes were divided into normal (NG) and high glucose (HG) groups, 4 liraglutide groups (Lir1–4), 3 Epac-1 agonist intervention groups (CPT1–3), and 2 Epac-1 shRNA transfection groups (sh21 and sh22). Apoptosis was measured using TUNEL assays, and the apoptotic indices were calculated. Intracellular ROS levels were measured using a DCFH-DA probe. Epac-1, Akt, and P-Akt (Ser473) expression were measured by immunoblotting.

Results: The apoptotic index and intracellular ROS levels were higher in the HG than NG group (P<0.01). Liraglutide decreased both parameters in a dose- and time-dependent manner. Liraglutide increased the expression of Epac-1 in the myocardium of diabetic rats and H9c2 cells (P<0.05), and increased Akt phosphorylation in the myocardium of diabetic rats (P<0.05). Liraglutide treatment also increased the P-Akt (Ser473)/Akt ratio (P<0.05). An Epac-1 agonist increased Epac-1 expression (P<0.05) and the P-Akt (Ser473)/Akt ratio (P<0.05) in a dose-dependent manner, and subsequently decreased apoptosis and intracellular ROS. Conversely, Epac-1shRNA knocked-down Epac-1 expression (P<0.01) and decreased the P-Akt (Ser473)/Akt ratio (P<0.05), but had no effect on apoptosis and intracellular ROS levels.

Conclusions: Liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway.

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