title: Interaction of epoxyeicosatrienoic acids and adipocyte fatty acid-binding protein in the modulation of cardiomyocyte contractility.
abstract: BACKGROUND
  Adipocyte fatty acid-binding protein (FABP4) is a member of a highly conserved family of cytosolic proteins that bind with high affinity to hydrophobic ligands, such as saturated and unsaturated long-chain fatty acids and eicosanoids. Recent evidence has supported a novel role for FABP4 in linking obesity with metabolic and cardiovascular disorders. In this context, we identified FABP4 as a main bioactive factor released from human adipose tissue that directly suppresses heart contraction in vitro. As FABP4 is known to be a transport protein, it cannot be excluded that lipid ligands are involved in the cardiodepressant effect as well, acting in an additional and/or synergistic way.
  
  
  OBJECTIVE
  We investigated a possible involvement of lipid ligands in the negative inotropic effect of adipocyte factors in vitro.
  
  
  RESULTS
  We verified that blocking the CYP epoxygenase pathway in adipocytes attenuates the inhibitory effect of adipocyte-conditioned medium (AM) on isolated adult rat cardiomyocytes, thus suggesting the participation of epoxyeicosatrienoic acids (EETs) in the cardiodepressant activity. Analysis of AM for EETs revealed the presence of 5,6-, 8,9-, 11,12- and 14,15-EET, whereas 5,6-EET represented about 45% of the total EET concentration in AM. Incubation of isolated cardiomyocytes with EETs in similar concentrations as found in AM showed that 5,6-EET directly suppresses cardiomyocyte contractility. Furthermore, after addition of 5,6-EET to FABP4, the negative inotropic effect of FABP4 was strongly potentiated in a concentration-dependent manner.
  
  
  CONCLUSIONS
  These data suggest that adipocytes release 5,6-EET and FABP4 into the extracellular medium and that the interaction of these factors modulates cardiac function. Therefore elevated levels of FABP4 and 5,6-EET in obese patients may contribute to the development of heart dysfunction in these subjects.
authors.affiliation: Medical Clinic III, University of Technology Dresden, Dresden, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Lamounier-Zepter
authors.affiliation: Medical Clinic III, University of Technology Dresden, Dresden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Look
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: W-H
authors.initials: WH
authors.lastname: Schunck
authors.affiliation: Medical Clinic III, University of Technology Dresden, Dresden, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Schlottmann
authors.affiliation: Medical Clinic III, University of Technology Dresden, Dresden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Woischwill
authors.affiliation: Medical Clinic III, University of Technology Dresden, Dresden, Germany.
authors.forename: S R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Morano
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051381:Rats
chemical_list: C493410:FABP4 protein, human; C524662:FABP4 protein, rat; D050556:Fatty Acid-Binding Proteins; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid