Interaction of epoxyeicosatrienoic acids and adipocyte fatty acid-binding protein in the modulation of heart function

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. Recent evidence has supported a novel role for FABP4 in linking obesity with metabolic and cardiovascular disorders. In this context, we verified in previous studies a direct bioactive impact of FABP4 on heart function. We demonstrated that human adipocytes release factors that directly suppress heart contraction in vitro. Subsequently, we identified FABP4 as the main cardiodepressant factor. Since 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 synergetic way. Therefore, we investigated in the present study a possible involvement of lipid ligands on the negative inotropic effect of adipocyte-factors in interaction with FABP4 in vitro. First, 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 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 cardiomyocytes contractility. Furthermore, after addition of 5,6-EET to FABP4, the negative inotropic effect of FABP4 was strongly potentiated in a concentration-dependent manner. These data suggest that adipocytes release 5,6-EET and FABP4 into the extracellular medium and the interaction of these factors modulates the cardiac function. Therefore, elevated levels of FABP4 and 5,6-EET in obese subjects may partially explain the development of heart dysfunction in those subjects.