Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A ₂

Abstract

Objective-Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a predictor for incident atherosclerotic disease. We investigated the effect of 3 hypolipidemic drugs that exert their action through different mechanisms on plasma and lipoprotein-associated Lp-PLA 2 activity and mass. Methods and Results-In 50 patients with Type IIA dyslipidemia were administered rosuvastatin (10 mg daily), whereas in 50 Type IIA dyslipidemic patients exhibiting intolerance to previous statin therapy were administered ezetimibe as monotherapy (10 mg daily). Fifty patients with Type IV dyslipidemia were given micronised fenofibrate (200 mg daily). Low-and high-density lipoprotein (LDL and HDL, respectively) subclass analysis was performed electrophoretically, whereas lipoprotein subfractions were isolated by ultracentrifugation. Ezetimibe reduced plasma Lp-PLA 2 activity and mass attributable to the reduction in plasma levels of all LDL subfractions. Rosuvastatin reduced enzyme activity and mass because of the decrease in plasma levels of all LDL subfractions and especially the Lp-PLA 2 on dense LDL subfraction (LDL-5 Key Words: hyperlipidemia Ⅲ lipoproteins Ⅲ PAF-acetylhydrolase Ⅲ Lp-PLA 2 Ⅲ ezetimibe Ⅲ fenofibrate Ⅲ rosuvastatin P latelet-activating factor (PAF) acetylhydrolase exhibits a Ca 2ϩ -independent phospholipase A 2 activity and degrades PAF and oxidized phospholipids by catalyzing the hydrolysis of the ester bond at the sn-2 position. 1 PAF-acetylhydrolase in plasma is complexed to lipoproteins 2 ; thus it is also referred as lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ). 3 Lp-PLA 2 is associated mainly with apolipoprotein B (apoB)-containing lipoproteins and primarily with low-density lipoprotein (LDL), whereas a small proportion of circulating enzyme activity is also associated with high-density lipoprotein (HDL). 1,2 ⌻he majority of the LDL-associated Lp-PLA 2 activity is bound to the atherogenic small-dense LDL (sdLDL) particles, 2,4,5 and we recently showed that the enzyme activity is a marker of sdLDL particles in plasma. 6 Lp-PLA 2 is principally produced by hematopoietic cells including monocytes-macrophages. 7,8 Lp-PLA 2 has been identified in atherosclerotic plaques 9 ; however, its role in atherosclerosis is still under investigation. In this regard, it is suggested that this enzyme might have an antiinflammatory role because it degrades and inactivates proinflammatory PAF and oxidized phospholipids 10,11 ; other studies showed that Lp-PLA 2 may have a proinflammatory and proatherogenic role 12 because it generates lysophosphatidylcholine (lysoPC) 3,13 and bioactive oxidized fatty residues. 3 Data from large White population studies demonstrated an independent association between plasma Lp-PLA 2 with cardiovascular disease (CVD) risk. In this regard a recent metaanalysis showed that Lp-PLA 2 is significantly associated with CVD, and the risk estimate appears to be relatively unaffected by adjustment for conventional CVD risk factors. 14 In contrast to total plasma enzyme, which mainly represents ...

Relationship of Lipoprotein-Associated Phospholipase A2 Mass and Activity with Incident Vascular Events among Primary Prevention Patients Allocated to Placebo or to Statin Therapy: An Analysis from the JUPITER Trial

“…That Lp-PLA 2 levels did not modify the benefit of statin therapy may again reflect tight linkage between apo B, LDL-C, non-HDL-C, and Lp-PLA 2 . In prior work for simvastatin, pravastatin, rosuvastatin, ezetimibe, and fenofibrate (5,19,20 ), reductions in Lp-PLA 2 have been attributable in part to concomitant reductions in LDL-C or apo B.…”

Effect of Switching From Statin Monotherapy to Ezetimibe/Simvastatin Combination Therapy Compared With Other Intensified Lipid‐Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease

“…These results are in line with previous studies that showed reductions in Lp‐PLA 2 mass and activity with statins and ES were proportionate to the extent of LDL‐C lowering efficacy25, 58, 59 and that combination ezetimibe therapy with rosuvastatin and simvastatin provided additional reductions in Lp‐PLA 2 mass and activity in patients already receiving statin monotherapy 58. Ezetimibe, rosuvastatin, and fenofibrate monotherapies have been shown to primarily reduce Lp‐PLA 2 activity and mass associated with LDL lipoprotein subfractions via receptor‐mediated uptake 60. On the other hand, it has also been suggested that statin and nonstatin lipid‐lowering therapies reduce Lp‐PLA 2 through a receptor‐independent clearance mechanism and that Lp‐PLA 2 changes are weakly correlated with LDL‐C changes, indicating that Lp‐PLA 2 reduction is only partly explained by LDL‐C lowering 61.…”

The elevation of apoB in hypercholesterolemic patients is primarily attributed to the relative increase of apoB/Lp-PLA2

“…phase 3 trials on a selective enzyme inhibitor, darapladib, are currently in progress ( 15 ). Furthermore, previous studies by our group ( 16,17 ) and others (18)(19)(20) have demonstrated that among existing cardiovascular drugs, statins effectively reduce plasma levels of Lp-PLA 2 activity and mass in parallel with the signifi cant reduction of LDL-cholesterol levels, suggesting that the rate of LDL removal from the circulation may represent an important mechanism for the reduction of plasma Lp-PLA 2 levels ( 16,17 ).…”