A-002 (Varespladib), a phospholipase A ₂ inhibitor, reduces atherosclerosis in guinea pigs

Abstract

Background

The association of elevated serum levels of secretory phospholipase A ₂ (sPLA ₂) in patients with cardiovascular disease and their presence in atherosclerotic lesions suggest the participation of sPLA ₂ enzymes in this disease. The presence of more advanced atherosclerotic lesions in mice that overexpress sPLA ₂ enzymes suggest their involvement in the atherosclerotic process. Therefore, the sPLA ₂ family of enzymes could provide reasonable targets for the prevention and treatment of atherosclerosis. Thus, A-002 (varespladib), an inhibitor of sPLA ₂enzymes, is proposed to modulate the development of atherosclerosis.

Methods

Twenty-four guinea pigs were fed a high saturated fat, high cholesterol diet (0.25%) for twelve weeks. Animals were treated daily with A-002 (n = 12) or vehicle (10% aqueous acacia; n = 12) by oral gavage. After twelve weeks, animals were sacrificed and plasma, heart and aorta were collected. Plasma lipids were measured by enzymatic methods, lipoprotein particles size by nuclear magnetic resonance, aortic cytokines by a colorimetric method, and aortic sinus by histological analyses.

Results

Plasma total cholesterol, HDL cholesterol and triglycerides were not different among groups. However, the levels of inflammatory cytokines interleukin (IL)-10, IL-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly reduced in the treatment group. This group also had a significant 27% reduction in cholesterol accumulation in aorta compared with placebo group. Morphological analysis of aortic sinus revealed that the group treated with A-002 reduced atherosclerotic lesions by 24%.

Conclusion

The use of A-002 may have a beneficial effect in preventing diet-induced atherosclerosis in guinea pigs.