Abstract
BackgroundLipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms.Methodology/Principal FindingsApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group.Conclusions/SignificanceInhibition of lp-PLA2 by darapladib leads to attenuation of in vivo inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis.
Highlights
Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke
We examined the effects of the lp-PLA2 inhibitor, darapladib, in ApoE-deficient mice to further establish its role in development of atherosclerosis
Darapladib inhibits mouse serum lp-PLA2 activity in vivo We examined a range of darapladib concentrations to determine the dose inducing inhibition of mouse plasma lp-PLA2 before continuous administration, and found the dosage of 50 mg/kg.p.o inhibits the plasma lp-PLA2 activity remarkably (Figure 1A)
Summary
Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. Lp-PLA2, designated platelet-activating factor acetylhydrolase (PAF-AH; E.C. 3.1.1.47), is a special Ca2+-independent phospholipase associated mainly with apoB-containing lipoproteins and primarily with LDL in humans [2]. There is considerable evidence to support regulatory roles of these two products, lysoPCs, in promoting atherosclerotic plaque development. The in vitro and ex vivo findings collectively suggest a causative role of lp-PLA2 in the development of atherosclerosis, and inhibition of its activity may induce beneficial effects. An earlier study reported that the lp-PLA2 inhibitor, darapladib, reduces complex coronary atherosclerotic plaque development in pigs with induced diabetes and hypercholesterolemia [7]. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. We evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms
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