Abstract
BACKGROUND: Endothelial dysfunction and injury are thought to play an important role in progression of coronary-artery-disease (CAD). High-density-lipoprotein from healthy subjects (HDLHealthy) has been proposed to exert endothelial anti-apoptotic effects that may represent an important anti-atherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDLCAD and HDLHealthy on activation of endothelial anti- and pro-apoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes. METHODS AND RESULTS: HDL was isolated from patients with stable CAD (HDLsCAD), an acute coronary syndrome (HDLACS) and healthy subjects. HDLHealthy induced expression of the endothelial anti-apoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apoE-deficient-mice in vivo. In contrast, HDLsCAD and HDLACS did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL and stimulated endothelial pro-apoptotic pathways, in particular p38-MAPK-mediated activation of the pro-apoptotic Bcl-2-protein tBid. Endothelial anti-apoptotic effects of HDLHealthy were observed after inhibition of endothelial nitric-oxide-synthase and after delipidation, but not completely mimicked by apoA-I or reconstituted HDL, suggesting an important role of the HDL-proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin- and increased apoC-III-content of HDLsCAD and HDLACS as mechanisms leading to altered effects on endothelial apoptosis. CONCLUSIONS: The present study demonstrates for the first time that HDLCAD does not activate endothelial anti-apoptotic pathways, but rather stimulates potential endothelial pro-apoptotic pathways. HDL-proteome remodeling plays an important role for these altered functional properties of HDL. These findings provide novel insights into mechanisms leading to altered vascular effects of HDL in coronary disease.
Riwanto, Meliana