Abstract 241: Anti-Inflammatory Properties of Cynomolgus Monkey and Rabbit High-Density Lipoprotein Following Treatment With Recombinant Lecithin Cholesterol Acyltransferase

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Introduction: Lecithin cholesterol acyltransferase (LCAT) modulates HDL formation and increases HDL-C. Anti-inflammatory properties of HDL may be atheroprotective. We evaluated HDL from rabbits and cynomolgus monkeys treated with recombinant LCAT (rLCAT) to determine its anti-inflammatory properties. Methods: HDL from serum was isolated by ultracentrifugation. HUVECs were treated with HDL, stimulated with TNFα, and mRNA expression of VCAM-1, E-Selectin, and ICAM-1 was measured. Results: TNFα induced adhesion molecule expression in HUVECs treated with HDL (0.3 mg/mL) from rLCAT treated rabbits was reduced (E-Selectin) or similar (VCAM-1, ICAM-1) compared to pre-dose HDL. Using HDL (0.3 mg/mL) from rLCAT treated cynomolgus monkeys reduced expression of E-Selectin, VCAM-1, and ICAM-1 compared to control (pre-dose or vehicle) HDL in a rLCAT dose-dependent manner. In HUVECs treated with cynomolgus monkey HDL at concentrations normalized to serum HDL-C, adhesion molecule expression was reduced but showed a different profile. HDL after treatment with 1 or 5 mpk rLCAT reduced expression more than HDL from controls, while HDL after treatment with 20 or 150 mpk rLCAT blocked expression less than controls. Conclusions: HDL from rabbits and cynomolgus monkeys after rLCAT treatment was equally or more anti-inflammatory compared to control HDL when tested at a fixed concentration, a measure of HDL quality. To account for treatment changes to both HDL quality and quantity, HDL was tested relative to serum HDL-C. In this case, HDL from the 1 mpk group proved most efficacious in reducing TNFα stimulated adhesion molecule expression compared to vehicle HDL or HDL from higher doses.