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.
Highlights
Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS)
Median Lp(a) concentrations were
After statin treatment for 180 days, plasma LDL-C levels decreased by 37% (P < 0.0001), TGs by 41% (P < 0.0005), and apoB by 29% (P < 0.0001); by contrast, despite small increments, there was no significant change in HDL-C, apoAI, or Lp(a) upon treatment (Table 2)
Summary
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. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the aforementioned funding bodies. 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.—Orsoni, A., P. By virtue of efficacious lowering of circulating levels of LDL-cholesterol (LDL-C), statins, or HMG-CoA inhibitors, stabilize vulnerable, lipid-rich atherosclerotic plaques, Abbreviations: AA, arachidonic acid; AAPH, 2,2′-azobis(2-methylpropionamidine) dihydrochloride; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FC, free cholesterol; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; LOOH, lipid hydroperoxide; Lp(a), lipoprotein (a); MetS, metabolic syndrome; PC, phosphatidylcholine; PC(O), alkylphosphatidylcholine; PCOH, phospholipid hydroxide; PCOOH, phospholipid hydroperoxide; PC-P, phosphatidylcholine plasmalogen; PC(P), alkenylphosphatidylcholine; PE, phosphatidylethanolamine; PE(O), alkylphosphatidylethanolamine; PE-P, phosphatidylethanolamine plasmalogen; PE(P), alkenylphosphatidylethanolamine; PL, phospholipid; PUPC, polyunsaturated phosphatidylcholine; ROS, reactive oxygen species; SBP, systolic blood pressure; TP, total protein content
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