IMPACT OF EXOGENOUS APELINERGICS ON METABOLIC DYSFUNCTION IN EXPERIMENTAL SEPTIC HEARTS
CCC ePoster Library. Delile E. 10/26/19; 280314; 256
Dr. Eugénie Delile
Dr. Eugénie Delile
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BACKGROUND: ELABELA (ELA) and Apelin-13 (APL-13) bind to the apelin receptor (APJ), a GPCR highly expressed in the cardiovascular system. Those are the strongest known endogenous inotropic and dominant apelinergic ligands in human heart which improve heart performance during sepsis. Apelins (APL) have been also clearly committed in improving insulin sensitivity and glucose handling, including in the heart. The purpose of this study was to establish the metabolic profile and the impact of APL infusion in an experimental model of rat septic shock.

METHODS AND RESULTS: Sepsis-related myocardial dysfunction was induced by cecal ligation & puncture (CLP) and apelinergic's infusions (APL-13 15µg/kg/hr, ELA 39µg/kg/hr) or saline resuscitation (2.5mL/kg/hr) started afterwards for 24hrs. Metabolic profile in vivo was evaluated by indirect calorimetric assays (Promethion) and euglycemic-hyperinsulinic clamp, and arterial lactates measured. The major cellular glucose transporter GLUT4 and fatty acid transporter FATP6 expression and dynamic membrane translocation under these APL exposures were investigated by membrane separation ultracentrifugation and Western blotting (in whole hearts) and by confocal fluorescence microscopy in rat neonatal ventricular cardiomyocytes (RNVC) with or without induced human APJ overexpression. In these cells and under different conditions, mitochondrial respiration was also studied by Seahorse system. Arterial lactates rose 24h after CLP, but less with apelinergic infusions. CLP induced a significant decrease of the respiratory quotient (RQ) in the dark phase, as defined by the ratio of CO2 production (VCO2)/O2 consumption (VO2), and of energy expenditure (EE). APL-13 infusion enhanced RQ and EE energy. Substrates utilization calculated from the RQ after CLP induction revealed a metabolic switch from a major use of fatty acids to a higher use of carbohydrates with APL infusions. CLP provoked a significant decrease of glucose infusion rate necessary to maintain euglycemia. GLUT4 overall myocardial expression slightly down-regulated 24hrs after CLP was not clearly affected by apelinergic infusions. FATP6 myocardial expression was up-regulated 24hrs after CLP and only affected by ELA infusion. RNVC basal respiration and ATP production appeared to be modulated by apelinergic exposure.

CONCLUSION: CLP induced major metabolic changes and apelinergic system modulation had an impact on this profile. The next perspective of this study will be to evaluate the impact of APL infusion on the energy metabolism of septic heart in PET imaging. This project could provide proof of concept for a new therapy on the management of metabolic disorders and cardiomyopathy associated with sepsis.
BACKGROUND: ELABELA (ELA) and Apelin-13 (APL-13) bind to the apelin receptor (APJ), a GPCR highly expressed in the cardiovascular system. Those are the strongest known endogenous inotropic and dominant apelinergic ligands in human heart which improve heart performance during sepsis. Apelins (APL) have been also clearly committed in improving insulin sensitivity and glucose handling, including in the heart. The purpose of this study was to establish the metabolic profile and the impact of APL infusion in an experimental model of rat septic shock.

METHODS AND RESULTS: Sepsis-related myocardial dysfunction was induced by cecal ligation & puncture (CLP) and apelinergic's infusions (APL-13 15µg/kg/hr, ELA 39µg/kg/hr) or saline resuscitation (2.5mL/kg/hr) started afterwards for 24hrs. Metabolic profile in vivo was evaluated by indirect calorimetric assays (Promethion) and euglycemic-hyperinsulinic clamp, and arterial lactates measured. The major cellular glucose transporter GLUT4 and fatty acid transporter FATP6 expression and dynamic membrane translocation under these APL exposures were investigated by membrane separation ultracentrifugation and Western blotting (in whole hearts) and by confocal fluorescence microscopy in rat neonatal ventricular cardiomyocytes (RNVC) with or without induced human APJ overexpression. In these cells and under different conditions, mitochondrial respiration was also studied by Seahorse system. Arterial lactates rose 24h after CLP, but less with apelinergic infusions. CLP induced a significant decrease of the respiratory quotient (RQ) in the dark phase, as defined by the ratio of CO2 production (VCO2)/O2 consumption (VO2), and of energy expenditure (EE). APL-13 infusion enhanced RQ and EE energy. Substrates utilization calculated from the RQ after CLP induction revealed a metabolic switch from a major use of fatty acids to a higher use of carbohydrates with APL infusions. CLP provoked a significant decrease of glucose infusion rate necessary to maintain euglycemia. GLUT4 overall myocardial expression slightly down-regulated 24hrs after CLP was not clearly affected by apelinergic infusions. FATP6 myocardial expression was up-regulated 24hrs after CLP and only affected by ELA infusion. RNVC basal respiration and ATP production appeared to be modulated by apelinergic exposure.

CONCLUSION: CLP induced major metabolic changes and apelinergic system modulation had an impact on this profile. The next perspective of this study will be to evaluate the impact of APL infusion on the energy metabolism of septic heart in PET imaging. This project could provide proof of concept for a new therapy on the management of metabolic disorders and cardiomyopathy associated with sepsis.
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