The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002)

Abstract

Secretory phospholipase A2 (sPLA 2 ) activity promotes foam cell formation, increases proinflammatory bioactive lipid levels, decreases HDL levels, increases atherosclerosis in transgenic mice, and is an independent marker of cardiovascular disease. The effects of the sPLA 2 inhibitor A-002 (varespladib) and pravastatin as monotherapies and in combination on atherosclerosis, lipids, and paraoxonase (PON) activity in apoE 2/2 mice were investigated. Male apoE 2/2 mice were placed on a 12-week high-fat diet supplemented with A-002 alone or combined with pravastatin. Atherosclerotic lesions were examined for size and composition using en face analysis, Movat staining, anti-CD68, and anti-a actin antibodies. Plasma lipids and PON activity were measured. A-002 decreased atherosclerotic lesion area by ?75% while increasing fibrous cap size by over 200%. HDL levels increased 40% and plasma PON activity increased 80%. Pravastatin monotherapy had no effect on lesion size but when combined with A-002, decreased lesion area 50% and total cholesterol levels 18% more than A-002 alone. A-002, a sPLA 2 inhibitor, acts synergistically with pravastatin to decrease atherosclerosis, possibly through decreased levels of systemic inflammation or decreased lipid levels. A-002 treatment also resulted in a profound increase in plasma PON activity and significantly larger fibrous caps, suggesting the formation of more stable plaque architecture.-Shaposhnik, Z., X. Wang, J. Trias, H. Fraser, and A. J. Lusis. The synergistic inhibition of atherogenesis in apoE 2/2 mice between pravastatin and the sPLA 2 inhibitor varespladib (A-002

Lipoprotein-Associated and Secreted Phospholipases A 2 in Cardiovascular Disease

“…91 In a guinea pig model in which sPLA 2 -IIA and other isoforms are expressed, treatment with varespladib did not change plasma cholesterol levels but reduced aortic lipid accumulation. 90 The fact that varespladib exerts an antiatherogenic effect in C57BL/6 apoE Ϫ/Ϫ mice that do not express sPLA 2 -IIA suggests that sPLA 2 -V, sPLA 2 -X, or both contribute to atherosclerosis and are targeted in vivo by this inhibitor.…”

“…Varespladib has been shown to significantly reduce atherosclerosis by 40% to 75% in apoE Ϫ/Ϫ mice fed a high-fat diet 89,90 and to attenuate the development of angiotensin II-induced aortic aneurysms. 89 However, in 1 of the 2 studies in apoE Ϫ/Ϫ mice, 89 plasma total cholesterol was also decreased, which may contribute to the atheroprotective effect of varespladib.…”

Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome

“…5 Varespladib methyl is a nonspecific pan-sPLA 2 inhibitor with favorable effects on atherosclerotic lesions in animal studies. 11 Initial studies demonstrated that varespladib reduced levels of sPLA 2 -IIA by more than 90%, in addition to lowering low-density lipoprotein cholesterol (LDL-C) and Creactive protein (CRP) in patients with stable coronary disease and ACS. [12][13][14] The Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) study was designed to evaluate the effects of varespladib on cardiovascular risk in patients with ACS.…”

Cosegregation of Aortic Root Atherosclerosis and Intermediate Lipid Phenotypes on Chromosomes 2 and 8 in an Intercross of C57BL/6 and BALBc/ByJ Low-Density Lipoprotein Receptor −/− Mice

“…Several studies in mice and humans have linked NURR1 and secretory phospholipase A2, the ligand of PLA2R1, to lipoprotein metabolism, lipolysis, foam cell formation, and development of atherosclerosis. [25][26][27][28] We investigated liver expression of both genes and performed expression QTL mapping in F2 mice to test whether we could detect significant differences in transcript levels based on allele status. Both genes were expressed in liver, but we did not detect significant expression differences or expression QTLs in F2 mice (Supplemental Figure III).…”