Abstract
Objectives: Lipoprotein(a)[Lp(a)] is a causal, genetic risk factor for cardiovascular disease(CVD) and is enriched in pro-inflammatory oxidized phospholipids(OxPL) and lipoprotein-associated phospholipase A2(Lp-PLA2). Epidemiologic outcome studies have shown that the OxPL, Lp(a) and Lp-PLA2 collectively mediate additive risk for CVD. Methods: To derive insights into the relationships between Lp(a), OxPL and Lp-PLA2, 18 patients with familial hypercholesterolemia(FH) and Low(<10mg/dl), Intermediate (∼50mg/dl) or High(>100mg/dl) Lp(a) levels on chronic LDL apheresis were evaluated. Twenty-five isopycnic density fractions(density <1.015 to >1.189 g/ml) were isolated from pre and post apheresis plasma(n=50 fractions per patient). OxPL and Lp-PLA2 mass and activity were quantitated with a variety of techniques under 3 conditions: in plasma, in each density fraction with direct plating techniques and on individual lipoproteins within each density fraction by using antibody capture assays to apoB-100(OxPL/apoB and Lp-PLA2/apoB), Lp(a)[OxPL/apo(a) and Lp-PLA2/apo(a)] and apoA-I(OxPL/apoA-I and Lp-PLA2/apoA-I)(total of 900 fractions per measure) and detecting OxPL and Lp-PLA2 with monoclonal antibodies E06 and 4B4, respectively. Results: In whole density gradients by direct plating techniques, OxPL were almost exclusively detected in the Lp(a) containing fractions(density 1.059-1.094 g/ml) and Lp-PLA2 mass and activity were present between the apoB and Lp(a) density fractions. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels; Lp-PLA2/apoB and Lp-PLA2/apoA-I levels were highest in patients with Low Lp(a) but decreased proportionally with increasing Lp(a) levels; Lp-PLA2/apo(a) was lowest in patients with Low Lp(a) levels and increased proportionally with increasing Lp(a) levels. LDL apheresis significantly reduces levels of OxPL and Lp-PLA2 on apoB and Lp(a), particularly in patients with high Lp(a) levels Conclusions: This study documents that OxPL are primarily present on Lp(a) and Lp-PLA2 primarily on apoB, but the proportion of each increases on Lp(a) and decreases on apoB as plasma Lp(a) levels increase. These data suggest a pathophysiological relationship between Lp(a), OxPL and Lp-PLA2 and provide a rationale for understanding how they collectively mediate CVD in humans.
Published Version
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