title: Exenatide Reduces Tumor Necrosis Factor-α-induced Apoptosis in Cardiomyocytes by Alleviating Mitochondrial Dysfunction.
abstract: BACKGROUND
  Tumor necrosis factor-α (TNF-α) plays an important role in progressive contractile dysfunction in several cardiac diseases. The cytotoxic effects of TNF-α are suggested to be partly mediated by reactive oxygen species (ROS)- and mitochondria-dependent apoptosis. Glucagon-like peptide-1 (GLP-1) or its analogue exhibits protective effects on the cardiovascular system. The objective of the study was to assess the effects of exenatide, a GLP-1 analogue, on oxidative stress, and apoptosis in TNF-α-treated cardiomyocytes in vitro.
  
  
  METHODS
  Isolated neonatal rat cardiomyocytes were divided into three groups: Control group, with cells cultured in normal conditions without intervention; TNF-α group, with cells incubated with TNF-α (40 ng/ml) for 6, 12, or 24 h without pretreatment with exenatide; and exenatide group, with cells pretreated with exenatide (100 nmol/L) 30 mins before TNF-α (40 ng/ml) stimulation. We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry, measured ROS production and mitochondrial membrane potential (MMP) by specific the fluorescent probes, and assessed the levels of proteins by Western blotting for all the groups.
  
  
  RESULTS
  Exenatide pretreatment significantly reduced cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay at 12 h and 24 h. Also, exenatide inhibited excessive ROS production and maintained MMP. Furthermore, declined cytochrome-c release and cleaved caspase-3 expression and increased bcl-2 expression with concomitantly decreased Bax activation were observed in exenatide-pretreated cultures.
  
  
  CONCLUSIONS
  These results suggested that exenatide exerts a protective effect on cardiomyocytes, preventing TNF-α-induced apoptosis; the anti-apoptotic effects may be associated with protection of mitochondrial function.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Cao
authors.forename: Zhang-Wei
authors.initials: ZW
authors.lastname: Chen
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Gao
authors.forename: Xing-Xu
authors.initials: XX
authors.lastname: Wang
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Shu-Fu
authors.initials: SF
authors.lastname: Chang
authors.affiliation: Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Ju-Ying
authors.initials: JY
authors.lastname: Qian
authors.forename: Jun-Bo
authors.initials: JB
authors.lastname: Ge
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D000077270:Exenatide; D020287:In Situ Nick-End Labeling; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D014688:Venoms; D000077270:Exenatide