Abstract 126: Effects of Rosuvastatin on the Protein Composition of Lipoprotein Subfractions

Abstract

Introduction: Statins, by inhibiting HMG-CoA reductase and up regulating hepatic LDL receptors, effectively lower plasma LDL-C by as much as 50%, thus reducing future CVD events. However, the physiological effects of statins are diverse and not all are related to lowering of LDL-C. Goal: The goal of this study was to test our hypothesis that some of these pleiotropic alternative effects from statins may be driven by compositional changes to lipoproteins distinct from their cholesterol content. We, therefore, performed a small clinical pilot study to assess the impact of statins on lipoprotein associated proteins in healthy individuals. Methods: Ten subjects with normal LDL-C (<130 mg/dL) were given rosuvastatin (20 mg/day) for 28 days. Plasma samples collected at baseline and after treatment were used for lipid measurement, nuclear magnetic resonance (NMR) lipoprotein profiling and lipoprotein proteomics. Results: The effects of rosuvastatin treatment on clinical lipid measures and NMR profile were consistent with established findings. Proteomic analysis of FPLC fractions representing LDL, HDL-1 (large) and HDL-2 (small) identified a total of 124 different proteins. Spectral counting was used to compare relative protein detection before and after statin therapy. Significant protein changes were found in each lipoprotein pool: LDL = 9, HDL-1 = 9 and HDL-2 = 4. These changes included both increases and decreases in proteins involved in lipoprotein metabolism, complement regulation and acute phase response. The most dramatic effect of the treatment was a profound increase in alpha-1-antirypsin (A1AT) spectral counts association with HDL-1 particles. Quantitative measurement by ELISA revealed an average 5.7 fold increase in HDL-1 associated A1AT. Preliminary in vitro studies indicate a potential functional role for A1AT enriched HDL in the formation of neutrophil extracellular traps (NETs), a pro-inflammatory component of vascular lesions. Summary: Based on these results, statins can significantly change the protein composition of both LDL and HDL. Some of these changes, such as the up regulation of A1AT on HDL, may convey anti-inflammatory functionality on lipoproteins and might contribute to some of the non-lipid lowering effects of statins.