title: Apelin regulates FoxO3 translocation to mediate cardioprotective responses to myocardial injury and obesity.
abstract: The increasing incidence of obesity accentuates the importance of identifying mechanisms and optimal therapeutic strategies for patients with heart failure (HF) in relation to obesity status. Here, we investigated the association between plasma level of apelin, an adipocyte-derived factor, and clinicopathological features of obese and non-obese patients with HF. We further explored potential regulatory mechanisms of cardiac cell fate responses in conditions combining myocardial injury and obesity. In a prospective, cross-sectional study involving patients with HF we show that obese patients (BMI ≥ 30 kg/m(2)) have higher left ventricular ejection fraction (LVEF) and greater levels of plasma apelin (p < 0.005) than non-obese patients (< 30 kg/m(2)), independently of ischemic etiology. In a mouse model combining ischemia-reperfusion (I/R) injury and high-fat diet (HFD)-induced obesity, we identify apelin as a novel regulator of FoxO3 trafficking in cardiomyocytes. Confocal microscopy analysis of cardiac cells revealed that apelin prevents nuclear translocation of FoxO3 in response to oxygen deprivation through a PI3K pathway. These findings uncover apelin as a novel regulator of FoxO3 nucleocytoplasmic trafficking in cardiac cells in response to stress and provide insight into its potential clinical relevance in obese patients with HF.
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: 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: 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: 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: Anne
authors.initials: A
authors.lastname: Drougard
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: Claude
authors.initials: C
authors.lastname: Knauf
authors.affiliation: Department of cardiology, Toulouse University Hospital, Toulouse, Cedex 9, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lagente
authors.affiliation: Department of cardiology, Toulouse University Hospital, Toulouse, Cedex 9, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Roncalli
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: Franck
authors.initials: F
authors.lastname: Desmoulin
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: 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: 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: Oksana
authors.initials: O
authors.lastname: Kunduzova
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000368:Aged; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006333:Heart Failure; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011446:Prospective Studies; D051381:Rats; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases