Abstract 13709: High-Density Lipoprotein is a Novel Activator of Cardiac Glucose Metabolism in both Healthy and Insulin Resistant Myocardium

Aims: High-density lipoprotein (HDL) is known to increase skeletal muscle glucose uptake, but whether this action extends to the myocardium and has relevance in the setting of ischemia is unknown. This study aimed to determine the effect of HDL on cardiac glucose metabolism both in vitro and in vivo, including during ischemia/reperfusion injury. Methods and Results: HDL treatment (50μg/mL) increased glucose uptake (147±10%), glycolysis (154±11%) and glucose oxidation (130±6%) in neonatal ventricular cardiomyocytes compared to saline control. HDL rapidly activated the Akt pathway and an Akt inhibitor (Akti 1/2) abolished HDL-mediated glucose uptake, suggesting an Akt-dependent mechanism. To determine the upstream receptor mechanism HDL binding to sphingosine-1-phosphate (S1P) receptors was blocked with either 1uM VPC23019 (S1P1&3 antagonist) or 1uM CAY10444 (S1P3 antagonist). Both similarly inhibited HDL-mediated glucose uptake. S1P is a known activator of the Akt pathway, thus our data suggests the S1P component of HDL increases glucose uptake via S1P3 activation of the Akt pathway. The effect of a single intravenous bolus of reconstituted HDL (CSL-111; 80mg/kg) in chow diet (CD) and high fat diet (HFD) insulin resistant C57Bl6 mice was investigated during an oral glucose tolerance test (OGTT). CSL-111 treatment increased cardiac muscle glucose clearance in both CD (168±16%) and HFD (138±11%) mice compared to saline infusion during the OGTT. To assess whether CSL-111 could increase cardiac glucose uptake in an ischemic setting, a single bolus of CSL-111 (80mg/kg) was given at the beginning of reperfusion in mice following left anterior descending artery (LAD) ligation. CSL-111 trended to increase cardiac glucose uptake ([18F]Fluorodeoxyglucose tracer and PET-CT imaging) by 66% (chow) and 81% (HFD) (treatment effect p=0.07) 1 hour post-reperfusion following LAD surgery. Furthermore, CSL-111 improved long term cardiac functional recovery. Conclusion: These data show that HDL increases glucose uptake and utilisation in the heart suggesting a role for HDL therapies in preserving functional myocardium subsequent to acute coronary ischemic syndromes.