title: Apelin-13 administration protects against ischaemia/reperfusion-mediated apoptosis through the FoxO1 pathway in high-fat diet-induced obesity.
abstract: Apelin-13, an endogenous ligand for the apelin (APJ) receptor, behaves as a potent modulator of metabolic and cardiovascular disorders. Here, we examined the effects of apelin-13 on myocardial injury in a mouse model combining ischaemia/reperfusion (I/R) and obesity and explored their underlying mechanisms.
  
  
  
  Adult male C57BL/6J mice were fed a normal diet (ND) or high-fat diet (HFD) for 6 months and then subjected to cardiac I/R. The effects of apelin-13 post-treatment on myocardial injury were evaluated in HFD-fed mice after 24 h I/R. Changes in protein abundance, phosphorylation, subcellular localization and mRNA expression were determined in cardiomyoblast cell line H9C2, primary cardiomyocytes and cardiac tissue from ND- and HFD-fed mice. Apoptosis was evaluated by TUNEL staining and caspase-3 activity. Mitochondrial ultrastructure was analysed by electron microscopy.
  
  
  
  In HFD-fed mice subjected to cardiac I/R, i.v. administration of apelin-13 significantly reduced infarct size, myocardial apoptosis and mitochondrial damage compared with vehicle-treated animals. In H9C2 cells and primary cardiomyocytes, apelin-13 induced FoxO1 phosphorylation and nuclear exclusion. FoxO1 silencing by siRNA abolished the protective effects of apelin-13 against hypoxia-induced apoptosis and mitochondrial ROS generation. Finally, apelin deficiency in mice fed a HFD resulted in reduced myocardial FoxO1 expression and impaired FoxO1 distribution.
  
  
  
  These data reveal apelin as a novel regulator of FoxO1 in cardiac cells and provide evidence for the potential of apelin-13 in prevention of apoptosis and mitochondrial damage in conditions combining I/R injury and obesity.
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Boal
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Andrei
authors.initials: A
authors.lastname: Timotin
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Roumegoux
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Chiara
authors.initials: C
authors.lastname: Alfarano
authors.affiliation: University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.|US006, Microsurgery Services, Toulouse, Cedex 4, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Calise
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Rodica
authors.initials: R
authors.lastname: Anesia
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Tronchere
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, Cedex 4, France.|University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: Oksana
authors.initials: O
authors.lastname: Kunduzova
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C495199:apelin-13 peptide