Lipoprotein-associated phospholipase A2: a target directed at the atherosclerotic plaque

Abstract

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂)is so named because it is found in human plasma largely associated with low-density lipoprotein (LDL). It is secreted by macrophages and able to hydrolyse oxidised fatty acids from oxidised phospholipids in LDL thereby releasing pro-atherogenic lysophosphatidylcholine and fatty acids. Inhibition of this enzyme activity was proposed to be antiatherogenic and this hypothesis has been confirmed both in vitro and in animal studies using specific inhibitors. In addition, the enzyme has been shown to be present in human atherosclerotic plaques and to be a potential risk factor for coronary heart disease in epidemiological studies. However, Lp-PLA₂ is identical to platelet-activating factor acetylhydrolase (PAF-AH), whose activity is regarded as antiatherogenic. The role of this enzyme in humans, represented as Lp-PLA₂ or PAF-AH, remains to be clarified. Specific and potent inhibitors of Lp-PLA₂ have been described and help address this question. This is a novel approach directed specifically towards processes in atherogenesis which take place in the artery wall. Innovative strategies for clinical development are required to progress novel molecular strategies such as this.