Abstract 21471: Proteomic Analysis of High Density Lipoprotein (HDL) in Patients With an Acute Coronary Syndrome Reveals a Markedly Changed HDL-Proteome as Compared to Healthy Subjects and Frequent Oxidative Post-Translational Modifications
Background: HDL has been proposed to become dysfunctional in patients with cardiovascular disease, however, the underlying mechanisms remain to be further defined. We used shotgun proteomics to characterize changes of the HDL proteome between patients with an acute coronary syndrome (ACS) and healthy subjects (HS) and aimed to evaluate functional implications of changes in the HDL proteome in ACS.
Methods and Results: HDL was isolated from patients with ACS and HS (n=20) by sequential ultracentrifugation. Isolated HDL was subjected to 1D-gel prefractionation followed by LC-ESI-MS/MS. 76 HDL-associated proteins were identified, including all the apolipoproteins known to reside within HDL and several complement-regulatory proteins. Notably, acute phase response and inflammation-related proteins were substantially enriched in HDL from patients with ACS. These included serum amyloid A (SAA), complement C3 and complement C9, as quantified by spectral counting. Using gene ontology analysis, we identified several HDL-associated proteins that play important roles in the coagulation pathway, platelet activation, apoptosis, as well as angiogenesis. Furthermore, our analysis of post-translational modifications of HDL-associated proteins identified marked increase of oxidative modifications, i.e. substantially elevated levels of nitrotyrosine and methionine oxidation in HDL-bound proteins from patients with ACS, supporting the concept that oxidative modifications contribute importantly to generation of dysfunctional HDL in ACS. Consistent with these findings, HDL from patients with ACS was found to lose endothelial protective effects, i.e. did not inhibit endothelial cell apoptosis, in marked contrast to HDL from HS.
Conclusions: Importantly, the present study demonstrates a marked change of the HDL proteome in patients with acute coronary syndrome, in particular enrichment of acute phase response proteins and inflammation-related proteins, and a substantial increase of oxidative post-translational modifications of several HDL-associated proteins. These findings suggest that HDL is remodeled towards a pro-inflammatory lipoprotein in ACS and supports the role of oxidative modifications in generation of dysfunctional HDL in ACS.
- © 2010 by American Heart Association, Inc.