title: The GLP-1 analogue liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway.
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.
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormones and Development (Ministry of Health) Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: X-M
authors.initials: XM
authors.lastname: Wu
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormones and Development (Ministry of Health) Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Q-Y
authors.initials: QY
authors.lastname: Ou
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormones and Development (Ministry of Health) Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormones and Development (Ministry of Health) Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormones and Development (Ministry of Health) Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069450:Liraglutide; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007004:Hypoglycemic Agents; C526973:Rapgef3 protein, rat; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose