Mansucript Supplemental figures version.pdf

Rationale: Elevated serum lipoprotein(a) [Lp(a)] levels are associated with increased cardiovascular disease risk. ABCA1-mediated cholesterol efflux from macrophages is believed to be an anti-atherogenic process. We recently identified plasminogen as a driver of ABCA1-mediated cholesterol efflux and showed that its action is inhibited by purified human Lp(a).

Objective:To determine the effects of Lp(a) in human serum on ABCA1 cholesterol efflux.

Methods and Results:Cholesterol efflux capacity (CEC) was measured with two different cell culture models using serum from a cohort of 76 patients with either low (<50 mg/dl) or high (>50 mg/dl) levels of Lp(a). Using cAMP-stimulated J774 macrophages or hamster kidney (BHK) fibroblasts overexpressing human ABCA1, we show that patients with high Lp(a) had lower CEC compared with that of patients with low Lp(a), (-30.6%; P=0.002 or -24.1%; P<0.001, respectively). In addition, total-serum CEC negatively correlated with Lp(a) levels (r=-0.433; P=0.0007 or r=-0.505; P=0.0011, respectively). This negative association persisted after adjusting for serum cholesterol, age, sex, and statin use in a multiple linear regression model (adjusted R²=0.413 or R²=0.405, respectively), and was strengthen when further adjusting for the interaction between Lp(a) and plasminogen levels (adjusted R²=0.465 or R²=0.409, respectively). Finally, we show that total-serum and isolated Lp(a) from patients with high Lp(a) inhibit plasminogen-mediated ABCA1 cholesterol efflux.

Conclusions:Total-serum CEC is reduced in patients with high Lp(a) levels. This is in part due to the inhibition of plasminogen-mediated ABCA1 cholesterol efflux by Lp(a). Our findings suggest a novel atherogenic role for Lp(a).