Abstract
Statins lower plasma cholesterol by as much as 50%, thus reducing future cardiovascular events. However, the physiological effects of statins are diverse and not all are related to low density lipoprotein cholesterol (LDL-C) lowering. We performed a small clinical pilot study to assess the impact of statins on lipoprotein-associated proteins in healthy individuals (n = 10) with normal LDL-C (<130 mg/dL), who were treated with rosuvastatin (20 mg/day) for 28 days. Proteomic analysis of size-exclusion chromatography isolated LDL, large high density lipoprotein (HDL-L), and small HDL (HDL-S) fractions and spectral counting was used to compare relative protein detection before and after statin therapy. Significant protein changes were found in each lipoprotein pool and included both increases and decreases in several proteins involved in lipoprotein metabolism, complement regulation and acute phase response. The most dramatic effect of the rosuvastatin treatment was an increase in α-1-antirypsin (A1AT) spectral counts associated with HDL-L particles. Quantitative measurement by ELISA confirmed an average 5.7-fold increase in HDL-L associated A1AT. Molecular modeling predictions indicated that the hydrophobic reactive center loop of A1AT, the functional domain responsible for its protease inhibitor activity, is likely involved in lipid binding and association with HDL was found to protect A1AT against oxidative inactivation. Cell culture experiments, using J774 macrophages, demonstrated that the association of A1AT with HDL enhances its antiprotease activity, preventing elastase induced production of tumor necrosis factor α. In conclusion, we show that statins can significantly alter the protein composition of both LDL and HDL and our studies reveal a novel functional relationship between A1AT and HDL. The up-regulation of A1AT on HDL enhances its anti-inflammatory functionality, which may contribute to the non-lipid lowering beneficial effects of statins.
Highlights
From the ‡Lipoprotein Metabolism Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; §Cell Biology Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; ¶Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
We report the impact of rosuvastatin treatment on the lipoprotein proteome in humans and found that several protein components of both low density lipoproteins (LDL) and high density lipoprotein (HDL) particles were affected by treatment
The majority of proteome effects on LDL were reductions in protein content, which likely reflect the overall reduction in LDL particle number associated with statin therapy
Summary
A perhaps overly simplistic but well accepted paradigm for the role of lipoproteins in the development CVD is that excess low density lipoproteins (LDL) promote CVD, by depositing cholesterol in atherosclerotic plaque, whereas high density lipoprotein (HDL) particles remove excess cholesterol and perhaps mediate other anti-atherogenic effects. This has been translated into the clinical setting in terms of diagnostic testing. Statins are a class of compounds that inhibit a key enzyme in cholesterol synthesis in the liver, namely HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) These compounds have indirect effects on cholesterol metabolism by upregulating hepatic expression of the LDL receptor. The mechanisms, by which statins mediate these so called pleiotropic effects on atherosclerosis are largely unknown
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