Varespladib: targeting the inflammatory face of atherosclerosis

Abstract

This editorial refers to ‘Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease’, by R.S. Rosenson et al., doi:10.1093/eurheartj/ehq374 Atherosclerosis is a complex disease and in its pathogenesis depends on the interaction between lipoproteins and inflammatory mediators.1 This interaction orchestrates the progression of atherosclerosis from its earliest stage when oxidized lipoproteins and leucocytes penetrate dysfunctional endothelium and enter the subendothelial space, right until the end of the process when the plaque becomes unstable and ruptures, leading to a clinical event. Whereas our pharmacological armatorium that targets the lipid component of the risk factor spectrum has been tremendously succesful with the clinical introduction of statins in the middle of the 1990s, drugs that target the inflammatory face of atherosclerosis have thus far been scarce. Among the wide range of chemokines, adhesion molecules, and pro-oxidative substances that affect macrophage recruitment into the arterial wall, members of the phospholipase A2 (PLA2) family have received considerable attention since their purification from human plasma lipoproteins in 1987.2 PLA2s are small and relatively stable ubiquitous enzymes that hydrolyse the sn -2-acyl bond of phospholipids in cell membranes as well as in lipoproteins. This enzymatic activity yields non-esterified fatty acids and lysophospholipids, which are precursors of various proinflammatory mediators including leukotrienes, eicosanoids, prostaglandins, and platelet-activating factors ( Figure 1A ).3 In addition, both circulating and lipoprotein-bound PLA2s play a role in lipoprotein remodelling by high-affinity binding to specific domains on LDLs and apolipoprotein B. Such modified or oxidized LDL particles bind with higher affinity to endothelial proteoglycans, facilitating the penetration of these atherogenic particles into the subendothelial matrix where they accumulate and trigger additional proinflammatory cascades. The recent large-scale meta-analysis of genome-wide association studies for plasma lipids …