The role of lipoprotein-associated phospholipase A2 in atherosclerosis may depend on its lipoprotein carrier in plasma

Abstract

Platelet-activating factor (PAF) acetylhydrolase exhibits a Ca(2+)-independent phospholipase A2 activity and degrades PAFas well as oxidized phospholipids (oxPL). Such phospholipids are accumulated in the artery wall and may play key roles in vascular inflammation and atherosclerosis. PAF-acetylhydrolase in plasma is complexed to lipoproteins; thus it is also referred to as lipoprotein-associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is primarily associated with low-density lipoprotein (LDL), whereas a small proportion of circulating enzyme activity is also associated with high-density lipoprotein (HDL). The majority of the LDL-associated Lp-PLA2 (LDL-Lp-PLA2) activity is bound to atherogenic small-dense LDL particles and it is a potential marker of these particles in plasma. The distribution of Lp-PLA2 between LDL and HDL is altered in various types of dyslipidemias. It can be also influenced by the presence of lipoprotein (a) [Lp(a)] when plasma levels of this lipoprotein exceed 30 mg/dl. Several lines of evidence suggest that the role of plasma Lp-PLA2 in atherosclerosis may depend on the type of lipoprotein particle with which this enzyme is associated. In this regard, data from large Caucasian population studies have shown an independent association between the plasma Lp-PLA2 levels (which are mainly influenced by the levels of LDL-Lp-PLA2) and the risk of future cardiovascular events. On the contrary, several lines of evidence suggest that HDL-associated Lp-PLA2 may substantially contribute to the HDL antiatherogenic activities. Recent studies have provided evidence that oxPL are preferentially sequestered on Lp(a) thus subjected to degradation by the Lp(a)-associated Lp-PLA2. These data suggest that Lp(a) may be a potential scavenger of oxPL and provide new insights into the functional role of Lp(a) and the Lp(a)-associated Lp-PLA2 in normal physiology as well as in inflammation and atherosclerosis. The present review is focused on recent advances concerning the Lp-PLA2 structural characteristics, the molecular basis of the enzyme association with distinct lipoprotein subspecies, as well as the potential role of Lp-PLA2 associated with different lipoprotein classes in atherosclerosis and cardiovascular disease.