Translational Studies of Lipoprotein-Associated Phospholipase A2 in Inflammation and Atherosclerosis

Abstract

Objectives To examine the role of lipoprotein-associated phospholipase A2 (Lp-PLA2/PLA2G7) in human inflammation and coronary atherosclerosis. Background Lp-PLA2 has emerged as a potential therapeutic target in coronary heart disease (CHD). Data supporting Lp-PLA2 are indirect and confounded by species differences; whether Lp-PLA2 is causal in CHD remains in question. Methods We examined inflammatory regulation of Lp-PLA2 during experimental endotoxemia in human, probed the source of Lp-PLA2 in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA2, with coronary artery calcification (CAC). Results In contrast to circulating TNFα and CRP, blood and monocyte Lp-PLA2 mRNA decreased transiently, and plasma Lp-PLA2 mass declined modestly during endotoxemia. In vitro, Lp-PLA2 expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foam like-cells. Despite only a marginal association of SNPs in PLA2G7 with Lp-PLA2 activity or mass, numerous PLA2G7 SNPs were associated with CAC. In contrast, several SNPs in CRP were significantly associated with plasma CRP levels but had no relation with CAC. Conclusions Circulating Lp-PLA2 did not increase during acute phase response in human, while inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA2. Common genetic variation in PLA2G7 is associated with sub-clinical coronary atherosclerosis. These data link Lp-PLA2 to atherosclerosis in human while highlighting the challenge in using circulating Lp-PLA2 as a biomarker of Lp-PLA2 actions in the vasculature.

The Effect of Darapladib Therapy for the Expression of Lp-PLA2 in Dyslipidemia and Type 2 Diabetes Mellitus Atherosclerosis Model

“…This expression pattern was seen on both dyslipidemia and type II diabetes mellitus condition. This study supports a previous scientific proof (in vitro study) that found Lp-PLA 2 formation is dramatically increased in an arterial blood vessel at the time of monocyte differentiation into macrophage which occurs in a much early (Cao et al, 1998;Ferguson et al, 2012).…”

“…mRNA Lp-PLA 2 expression pattern is significantly increased in 16 weeks experimental groups (both dyslipidemia and type II diabetes mellitus conditions). This findings support previous an in vitro study findings which found that the early phase of inflammation process (monocyte to macrophage pre-transformation phase), mRNA Lp-PLA 2 expression level are so low to be detected in the blood, mRNA Lp-PLA 2 expression will significantly increase in blood after macrophage maturation phase (longer observation period phase) (Ferguson et al, 2012). Even though there is a possibility that Lp-PLA 2 is produced by macrophage locally in aortic tissue can also contribute to half of circulating Lp-PLA 2 .…”

“…It is not right to use the circulating Lp-PLA 2 level as an independent biomarker which represents Lp-PLA 2 action in atherosclerotic tissue. In other words, mRNA expression and Lp-PLA 2 protein activity in the blood is a poor predictor of PLA2G7 action on the arterial plaque (Ferguson et al, 2012). This result showed a supporting evidence for that in vitro study and support the pro-inflammatory pro-atherogenic role of Lp-PLA 2 .…”

“…This value will be divided with the lowest value that is achieved to get the increased value of each sample. The obtained results were analyzed using 2 -ΔΔCt method (Hatoum et al, 2010;Goncalves et al, 2012).…”

Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2

“…Monocyte/macrophages are key players in both initiation and progression of atherosclerosis, and they have been proposed as new potential therapeutic targets for the prevention and treatment of this disease ( 42 ). We previously demonstrated that maturation of monocytes into macrophages is accompanied by dramatic increases in Lp-PLA 2 mRNA and protein ( 21,43 ); these observations were recently confi rmed ( 44 ). Treatment of macrophages with acetylated LDL generates foam cells in vitro and further increases Lp-PLA 2 expression ( 44 ), which is consistent with observations in human atherosclerotic plaques ( 45 ).…”