title: 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.
authors: Clinical Biochemistry Service, APHP, HUPS, Bicêtre University Hospital, Le Kremlin Bicêtre, France.
authors: Alexina
authors: 0000-0003-4250-6280
authors: A
authors: Orsoni
authors: Clinical Biochemistry Service, APHP, HUPS, Bicêtre University Hospital, Le Kremlin Bicêtre, France.|Lip(Sys) Department, Atherosclerosis: Cholesterol Homeostasis and Macrophage Trafficking, Paris-Sud University and Paris-Saclay University, Châtenay-Malabry, France.
authors: Patrice
authors: 0000-0002-7655-2229
authors: P
authors: Thérond
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors: Ricardo
authors: R
authors: Tan
authors: Service of Endocrinology-Metabolism and Cardiovascular Disease Prevention, Pitié-Salpêtrière University Hospital, Paris, France.
authors: Philippe
authors: P
authors: Giral
authors: INSERM UMR-S939, Dyslipidemia and Atherosclerosis, and University of Pierre and Marie Curie, Pitié-Salpêtrière University Hospital, Paris, France.
authors: Paul
authors: P
authors: Robillard
authors: INSERM UMR-S1166 and University of Pierre and Marie Curie, Pitié-Salpêtrière University Hospital, Paris, France.
authors: Anatol
authors: A
authors: Kontush
authors: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors: Peter J
authors: 0000-0002-2593-4665
authors: PJ
authors: Meikle
authors: Clinical Biochemistry Service, APHP, HUPS, Bicêtre University Hospital, Le Kremlin Bicêtre, France john.chapman@upmc.fr.|Service of Endocrinology-Metabolism and Cardiovascular Disease Prevention, Pitié-Salpêtrière University Hospital, Paris, France.|INSERM UMR-S939, Dyslipidemia and Atherosclerosis, and University of Pierre and Marie Curie, Pitié-Salpêtrière University Hospital, Paris, France.
authors: M John
authors: MJ
authors: Chapman
mesh_terms: D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000008:administration & dosage; D016632:Apolipoprotein A-I / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D011804:Quinolines / Q000008:administration & dosage*
chemical_list: C505693:APOA1 protein, human; D000975:Antioxidants; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011804:Quinolines; C108475:pitavastatin
keywords: antioxidative activity; high density lipoprotein 3; lipidomics; low density lipoprotein; metabolic syndrome disease; oxidative stress; phospholipid hydroxides; pitavastatin