Abstract 4870: Mechanisms Leading to Impaired Endothelial-vasoprotective Properties of High Density Lipoprotein (HDL) in Patients With Coronary Disease (CAD)

Abstract

Background: HDL-raising therapies are currently intensely evaluated as a potential novel therapeutic strategy in patients with CAD. However, vascular effects of HDL have been observed to be highly variable. The aim of the present study was therefore to characterize mechanisms leading to altered endothelial-vasoprotective properties of HDL in patients with CAD. Methods: HDL was isolated from patients with stable CAD (sCAD), an acute coronary syndrome (ACS) and healthy subjects (HS; n=20 –25) by sequential ultracentrifugation. The effects of HDL on endothelial nitric oxide (NO) production, endothelium-dependent, NO-mediated vasodilation, signaling pathways leading to eNOS activation and endothelial superoxide production (ESR spectroscopy analysis) were examined. HDL-associated paraoxonase (PON) activity/content and endothelial binding of HDL (radioactive 125I-labelling of HDL) were characterized. Moreover, the role of eNOS and PON for anti-inflammatory properties of HDL were determined. Results: HDL from HS, but not HDL from sCAD/ACS patients, potently stimulated endothelial NO production. HDL from HS increased endothelial Akt, eNOS-Ser1177-phosphorylation and eNOS-Thr495-dephosphorylation, that was not observed with HDL from sCAD/ACS patients. Endothelial binding capacity of HDL was markedly reduced in patients with CAD. PON activity was reduced (−62.2% and −70.4% vs. HS, P<0.001), whereas PON1 content was increased in HDL from sCAD/ACS patients as compared to HDL from HS, suggesting inactivation of HDL-associated PON in CAD. Inhibition of PON activity prevented the capacity of HDL from HS to stimulate Akt/eNOS phosphorylation, endothelial NO production, NO-dependent vasodilation and to exert anti-inflammatory effects. eNOS siRNA knockdown prevented anti-inflammatory effects of HDL from HS. Conclusion: The present study demonstrates that reduced endothelial binding of HDL and inactivation of HDL-associated paraoxonase are major mechanisms leading to impaired endothelial-vasoprotective and anti-inflammatory effects of HDL in CAD patients. HDL-targeted treatment approaches should therefore not only increase HDL levels, but likely more important, restore endothelial-vasoprotective properties of HDL.