Abstract 14796: Endotoxin Induced Cardiac Metabolic Shift is Controlled Through the Regulation of Fatty Acid Oxidation by a Beta-3 Adrenergic Receptor.

Background: The cardiac metabolic shift has been observed in failing heart for starvation of the energy. CPT1 is an enzyme which takes a fatty acid into mitochondria and dysfunction of CPT1 reduces myocardial mitochondria function and worsens heart failure.On the other hand, beta-3 adrenergic receptor (B3AR) which induces lipolysis expresses in failing heart. We considered whether β3AR regulation could influence CPT1 function in a septic heart. Methods and Results: We made a heart failure model by intraperitoneal injection of lipopolysaccharide (LPS) of 10 mg/kg into C57Bl/6 mice. We divided these subjects into 3 groups as 1mg/kg of the β3AR agonist CL316243 (CL), 1mg/kg of the β3AR selective antagonist SR59230A (SR) and 200μl of normal saline (NS). Kaplan-Meier analysis showed that 24 hour-survival rate was significantly improved in the SR. (the survival rate was 100% (SR), 60% (NS) and 20% (CL), n=10 of each). Echocardiography revealed decreased LVEF was observed at 6 hours after LPS and gradually restored within 24 hours. LVEF did not reduce in the SR (62.3±9.7%), whereas it got worse in the CL (32.5±6.4%) than that in the NS (47.1±6.2%). Myocardial ATP was preserved in the SR, while it was significantly decreased in the NS and the CL. Quantitative PCR analysis revealed that gene expressions associated with fatty acid oxidation (FAO) and mitochondrial function were improved in the SR; Cpt1 , an enzyme for free fatty acid intake to mitochondria to promote FAO, was upregulated in the SR. In addition, Pgc1α and Errα , which are transcriptional factors associated with mitochondrial biogenesis, were also improved in the SR. In contrast, those expressions were downregulated in the NS and the CL. Oil red o staining and electron microscopy of the septic heart showed that the deposition of lipid droplets which had not been utilized for energy in mitochondria was markedly increased in the CL, but significantly reduced in the SR. These results suggested the β3AR antagonist improved metabolic pathway of FAO and mitochondrial dysfunction. Conclusion: Blockade of the β3AR spared cardiac energy by ameliorating FAO and mitochondrial dysfunction through the improvement of CPT1 expression in a septic heart. The β3 AR is a novel metabolic target for endotoxin-induced heart failure. [ABSTRACT FROM AUTHOR]