Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties*

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

Common coding variant in SERPINA1 increases the risk for large artery stroke

“…Recent studies have provided evidence for an interaction between AAT and lipoproteins, including both LDL (37) and HDL (38,39). Binding of AAT to reconstituted HDL reduced the inhibitory capacity of AAT toward NE (39), and a similar effect was seen in our study when lipoproteins were removed from the plasma matrix.…”

“…Binding of AAT to reconstituted HDL reduced the inhibitory capacity of AAT toward NE (39), and a similar effect was seen in our study when lipoproteins were removed from the plasma matrix. Moreover, we noticed that allele-specific differences of the dissociation constant disappeared, supporting our hypothesis of an altered interaction of M1(V213) AAT with lipoproteins in the complex plasma environment.…”

High‐Density Lipoprotein Cholesterol Concentration and Acute Kidney Injury After Cardiac Surgery

“…Long‐term statin exposure increases HDL's anti‐inflammatory and antioxidant capacity 23, 26, 38. In our study, the strength of the association between high HDL cholesterol concentration and decreased AKI was greatest among patients receiving long‐term statin therapy, was related to dose of long‐term preoperative statin, and was enhanced among patients randomized to receive perioperative atorvastatin.…”

Protective Effects of Fluvastatin on Reproductive Function in Obese Male Rats Induced by High-Fat Diet through Enhanced Signaling of mTOR

“…Recently, statins have been found to exert biological effects on osteoporosis, inflammation and other diseases in addition to their hypocholesterolemic activities [29][30][31]. Furthermore, several studies have shown that treatment with statins can reduce reproductive damage induced by hypercholesterolemia, however, the mechanisms by which obesity impairs spermatogenic function and how statins help recover from obesity-induced damage in the testes, sperm parameters, sex hormones, and metabolism is still unclear [32].…”