A‐002, a secretory phospholipase A2 inhibitor, reduces cholesterol accumulation in aorta and aortic cytokines in guinea pigs

Abstract

Secretory phospholipase A2 enzymes (sPLA2) are involved with the generation of proinflammatory molecules such as leukotrienes and prostaglandins and are associated with atherosclerotic plaques. In this study we tested the effects of an sPLA2 inhibitor (A‐002) on aortic inflammatory cytokines and aortic lipid accumulation in a guinea pig atherosclerosis model. For this purpose, 24 male Hartley guinea pigs (12 per group) were fed a diet containing 0.25% dietary cholesterol to induce atherosclerosis, for 3 months. Animals were randomized into placebo (PL) or treated (A‐002) group, and gavaged daily either with vehicle (10% acacia, PL) or A‐002 (150 mg/kg/d, A‐002). At the end of 12 weeks, guinea pigs were sacrificed and blood was collected to measure plasma lipids and lipoprotein subfractions. The aorta was harvested for histological evaluation, measurement of inflammatory cytokines and lipid accumulation. Aortic cytokines including Interleukin (IL)‐2, IL‐10, IL‐12 and GMSCF measured by use of antibodies and Luminex technique were significantly lower (p < 0.05) in the A‐002 group. In addition, the A‐002 group had 26.5% lower cholesterol accumulation in the aorta (p < 0.05), but not in plasma, in association with a reduction in atherosclerotic lesion content in the aortic sinus. From these studies we conclude that A‐002 was effective in reducing atherosclerosis, as indicated by reductions in aortic cholesterol content, inflammatory cytokines and lesion content. [Study supported by Anthera Pharmaceuticals, Inc., San Mateo, CA].