Invited Paper BI-TuM9
When Good Cholesterol Goes Bad: Proteins at the Water:Lipid Interface

Tuesday, October 16, 2007, 10:40 am, Room 609

Apolipoproteins are amphipathic alpha helical proteins that play a key role in lipid transport in biological systems. HDL - the good form of blood cholesterol that protects against heart disease - is a complex of apolipoprotein A-I (apoA-I), free cholesterol, phospholipids and neutral lipids. Posttranslational oxidative modifications of apoA-I have been proposed to play a pathogenic role in atherosclerosis. Quantifying oxidized amino acids in atherosclerotic tissue proteins by isotope dilution gas chromatography mass spectrometry (GC-MS) has been used to assess oxidative stress in vivo and to investigate the biochemical pathways that contribute to inflammatory disease. These studies have identified myeloperoxidase, a heme protein secreted by activated phagocytes, as one important pathway for oxidizing HDL in the human artery wall. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) coupled with liquid chromatography is rapidly emerging as a powerful technique for pinpointing sites of amino acid oxidation within apolipoproteins. Oxidants generated by myeloperoxidase lead to the site specific oxidation of apoA-I, and these posttranslational modifications are associated with major impacts on the biological function of the proteins. We have recently used 2-dimensional liquid chromatography ESI-MS/MS to test the hypothesis that proteins implicated in inflammation might be enriched in the HDL of subjects with coronary artery disease (CAD). Our observations suggest that HDL carries a unique cargo of proteins in CAD subjects and that certain of these proteins might make previously unsuspected contributions to the anti-inflammatory properties of HDL.