Role of lipoprotein-associated phospholipase A₂ in leukocyte activation and inflammatory responses

Abstract 

Background

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is an emerging cardiovascular risk marker. To explore the biologic role of Lp-PLA₂ in atherosclerosis, we examined its expression and contribution to leukocyte activation under proatherogenic conditions.

Methods and results

Following the induction of diabetes and hypercholesterolemia in a porcine model, a rapid increase in plasma Lp-PLA₂ activity was observed at 1 month. This was accompanied by upregulated Lp-PLA₂ mRNA expression by peripheral blood mononuclear cells (PBMC) at 3 months, and elevated Lp-PLA₂ mRNA expression in coronary arteries at 6 months. These changes were paralleled by increased inflammatory responses by circulating PBMC (ICAM-1, IL-6), in coronary tissues (ICAM-1, VCAM-1), and the subsequent accumulation of inflammatory cells. In human PBMC, proinflammatory mediators augmented the synthesis and release of functional Lp-PLA₂. Furthermore, lysophosphatidylcholine (lysoPC), a product of Lp-PLA₂ activity, induced an increase in several inflammatory cytokines (IL-1β, IL-6, TNF-α) in a concentration-dependent manner. In contrast, Lp-PLA₂ inhibition (SB677116; 1μM) abrogated the inflammatory response elicited by oxidized LDL.

Conclusions

In an experimental model of diabetes and hypercholesterolemia, leukocyte activation was associated with augmented Lp-PLA₂ expression. In vitro, Lp-PLA₂ activity mediated leukocyte activation and inflammatory responses, whereas Lp-PLA₂ inhibition abolished inflammatory responses induced by oxidized LDL. Collectively, these observations support a proatherogenic role for Lp-PLA₂.

Keywords: Atherosclerosis, Hypercholesterolemia, Diabetes, Inflammation, Lipoprotein-associated phospholipase A₂