Abstract 411: Vasculoprotective Function of HDL from Cetp-deficient Subjects

Objective- Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyses the transfer of cholesteryl esters from HDL to the other plasma lipoproteins. Genetic deficiency of CETP is one of the known causes of primary hyperalphalipoproteinemia and represents a unique tool to evaluate how structural HDL alterations impact on HDL atheroprotective activity. Aim of the present study was to assess the vasculoprotective activity of HDL isolated from carriers of genetic CETP deficiency. Subjects and Methods- HDL and HDL subfractions were isolated from carriers of the R37X, Q165X and IVS7+1 CETP mutations and tested for their protein/lipid composition and their anti-inflammatory and NO-promoting activity in endothelial cells. Results- HDL and HDL3 from carriers proved to be as effective as control HDL in down-regulating cytokine-induced VCAM-1 expression and in enhancing eNOS expression in endothelial cells. Interestingly, carriers’ HDL2 were significantly more efficient than HDL2 from controls in inhibiting VCAM-1 and enhancing eNOS expression, likely due to their peculiar lipid composition and their higher content of apoE. On the contrary, carriers’ HDL and HDL subfractions were less effective than lipoproteins from controls in stimulating eNOS activation by phosphorylation and NO production, likely because of a reduced content of S1P in carriers’ HDL. Conclusions- Large, apoE-enriched HDL that accumulate in genetic CETP deficiency retain their ability to preserve endothelial cell homeostasis, supporting the use of pharmacological CETP inhibition to increase HDL levels and enhance HDL-mediated atheroprotection.