Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia

Abstract

Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS). The impact of statin treatment on the capacity of HDL to inactivate LDL-derived, redox-active phospholipid hydroperoxides (PCOOHs) in MetS is indeterminate. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males were treated with pitavastatin (4 mg/day) for 180 days, resulting in marked reduction in plasma TGs (-41%) and LDL-cholesterol (-38%), with minor effects on HDL-cholesterol and apoAI. Native plasma LDL (baseline vs. 180 days) was oxidized by aqueous free radicals under mild conditions in vitro either alone or in the presence of the corresponding pre- or poststatin HDL2 or HDL3 at authentic plasma mass ratios. Lipidomic analyses revealed that statin treatment i) reduced the content of oxidizable polyunsaturated phosphatidylcholine (PUPC) species containing DHA and linoleic acid in LDL; ii) preferentially increased the content of PUPC species containing arachidonic acid (AA) in small, dense HDL3; iii) induced significant elevation in the content of phosphatidylcholine and phosphatidylethanolamine (PE) plasmalogens containing AA and DHA in HDL3; and iv) induced formation of HDL3 particles with increased capacity to inactivate PCOOH with formation of redox-inactive phospholipid hydroxide. Statin action attenuated LDL oxidability Concomitantly, the capacity of HDL3 to inactivate redox-active PCOOH was enhanced relative to HDL2, consistent with preferential enrichment of PE plasmalogens and PUPC in HDL3.

Trial registration: ClinicalTrials.gov NCT01595828.

Keywords: antioxidative activity; high density lipoprotein 3; lipidomics; low density lipoprotein; metabolic syndrome disease; oxidative stress; phospholipid hydroxides; pitavastatin.

Fig. 1.

Formation of PCOOH expressed as % initial PC in total LDL (A), total LDL + HDL2 mixture (B), and total LDL + HDL3 mixture (C) before (D0) and after pitavastatin treatment for 180 days (D180).

Fig. 2.

Ratio of PCOOH formation to PC consumption after oxidation in total LDL (A), total LDL + HDL2 mixtures (B), and total LDL + HDL3 mixtures (C) before (D0) and after pitavastatin treatment for 180 days (D180). C (insert): Diene formation expressed in arbitrary units in total LDL + HDL3 mixtures before (D0) and after pitavastatin treatment for 180 days (D180). * P < 0.05 vs. D0.