Abstract 14981: Deletion of Fatty Acid Binding Protein-4 and -5 Exacerbate Cardiac Dysfunction Because of Insufficient Adenosine Triphosphate Production during Pressure Overload in Mice
Introduction: The heart requires a high level of energy supply to generate a large amount of adenosine triphosphate (ATP) for maintenance of its mechanical function. Fatty acid (FA) is central energy substrate for the ATP production while glucose utilization is dynamically regulated in response to cardiac stress such as pressure-overload. We recently reported that capillary endothelial FA binding protein-4 and -5 (FABP4/5) play a critical role in FA uptake in the heart. FA uptake was reduced by 30-40% in the heart in FABP4/5 DKO (double knockout) as compared with WT (wild-type) mice while glucose uptake was 20-fold higher in DKO mice. Metabolome analysis further revealed that PCr (creatine phosphate, reserve energy) was reduced by 30% in DKO hearts while ATP content was kept at a normal level. These findings imply that ATP production is diminished and replenished by PCr in DKO mice despite remarkable and compensatory glucose utilization.
Hypothesis: The remarkable change of cardiac energy substrates (shift from FA to glucose) in DKO mice influences cardiac function under pressure overload by transverse aortic constriction (TAC).
Results: Three weeks after TAC, 20% of DKO died while all of WT mice survived. Consistent with this, echocardiography revealed that fractional shortening of left ventricle was significantly reduced in DKO mice that showed more cardiac hypertrophy. We further assessed cardiac uptake of FA and glucose by using 125I-BMIPP and 18F-FDG, respectively. In the presence of TAC, FA uptake declined by 30% in WT mice and by 50% in DKO compared with WT at baseline. Glucose uptake was 10-fold higher in WT mice and 40-fold higher in DKO compared with WT at baseline. Metabolome profiling further showed that after a week of TAC, PCr was reduced by 40% in WT mice and by 80% in DKO compared with WT at baseline, indicating that pressure overload resulted in a depletion of energy substrates in DKO heart despite the robust increase in glucose uptake.
Conclusions: FABP4/5 are indispensable to maintain the continuous mechanical function of the heart during high-workload condition, implying the importance of FA uptake at basal condition because compensatory massive increase in glucose utilization is not sufficient to meet the heightened demand for ATP synthesis.
Author Disclosures: M.R. Syamsunarno: None. T. Iso: None. N. Koitabashi: None. M. Kurabayashi: None.
- © 2014 by American Heart Association, Inc.