Background and Aims

Elevated Lp(a) serum levels are associated with increased risk for atherosclerotic coronary artery disease and stroke. Here, we analyzed the effect of plasma Lp(a) levels on caspase-1 and the pro-inflammatory cytokines it processes. We further directly compare the molecular composition of Lp(a) and LDL isolated from the same donors as well as their pro-atherogenic and pro-inflammatory potential.

Methods

Human plasmas with varying Lp(a) levels and isolated Lp(a) and LDL were incubated with THP-1 macrophages for three hours and caspase-1 activation and the release of pro-inflammatory cytokines IL-1β, IL-1α, and IL-18 was measured. Molecular composition of Lp(a) and LDL isolated from the same donors was determined by lipidomics and proteomics approaches.

Results

Plasma Lp(a) levels ranging from 1.7 to 165.3 mg/dL correlated significantly with caspase-1 activity (r = 0.496), IL-18 (r = 0.496), and IL-1α (r = 0.447) in macrophages. IL-1β secretion correlated significantly with plasma triglycerides, and not with Lp(a) levels.

Lipidomics comparison of LDL and Lp(a) indicated that Lp(a) was significantly depleted of poly-unsaturated fatty acids in all lipid classes. Proteomics analyses revealed that Lp(a) is enriched in inflammation-associated proteins. Lp(a) from induced robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 compared to a mild induction upon incubation with LDL from the same donors.

Conclusions

Our data show that plasma Lp(a) levels directly correlate with inflammasome activation in macrophages, isolated Lp(a) induces stronger dose-dependent caspase-1 activation than LDL, and LDL and Lp(a) have clear structural differences additionally to apo(a).

Background and Aims

Elevated Lp(a) serum levels are associated with increased risk for atherosclerotic coronary artery disease and stroke. Here, we analyzed the effect of plasma Lp(a) levels on caspase-1 and the pro-inflammatory cytokines it processes. We further directly compare the molecular composition of Lp(a) and LDL isolated from the same donors as well as their pro-atherogenic and pro-inflammatory potential.

Methods

Human plasmas with varying Lp(a) levels and isolated Lp(a) and LDL were incubated with THP-1 macrophages for three hours and caspase-1 activation and the release of pro-inflammatory cytokines IL-1β, IL-1α, and IL-18 was measured. Molecular composition of Lp(a) and LDL isolated from the same donors was determined by lipidomics and proteomics approaches.

Results

Plasma Lp(a) levels ranging from 1.7 to 165.3 mg/dL correlated significantly with caspase-1 activity (r = 0.496), IL-18 (r = 0.496), and IL-1α (r = 0.447) in macrophages. IL-1β secretion correlated significantly with plasma triglycerides, and not with Lp(a) levels.

Lipidomics comparison of LDL and Lp(a) indicated that Lp(a) was significantly depleted of poly-unsaturated fatty acids in all lipid classes. Proteomics analyses revealed that Lp(a) is enriched in inflammation-associated proteins. Lp(a) from induced robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 compared to a mild induction upon incubation with LDL from the same donors.

Conclusions

Our data show that plasma Lp(a) levels directly correlate with inflammasome activation in macrophages, isolated Lp(a) induces stronger dose-dependent caspase-1 activation than LDL, and LDL and Lp(a) have clear structural differences additionally to apo(a).