Differential Expression of Lipoprotein-Associated Phospholipase A2 in Monocyte Subsets: Impact of Uremia and Atherosclerosis

Abstract

Background: Monocytic products, such as lipoprotein-associated phospholipase A2 (Lp-PLA2), may participate in the development of atherosclerosis. Heterogeneity of monocytes is widely acknowledged. Classical, intermediate, and non-classical subsets can be discerned. Recently, an inflammatory, pro-atherogenic monocyte population could be identified in hemodialysis patients. In this study, we investigated the expression of Lp-PLA2 on leucocytes and different monocyte subpopulations and their possible role in uremia, inflammation, and atherosclerosis. Methods: Chronic kidney disease stage 5-D (CKD5-D; n = 57), healthy control subjects with hs-C-reactive protein (CRP) levels ≤1 mg/L (CO-N, n = 22) and a control group with inflammatory activation (CRP levels >1 mg/L, CO-I, n = 29) were enrolled in this cross-sectional observation. The CKD5-D cohort was dichotomized into patients with (A+) and without subclinical atherosclerosis (A-) by carotid artery ultrasound measurement. Lp-PLA2 activity was determined in plasma samples, Lp-PLA2 mRNA expression analysis in leucocytes, and sorted monocyte subsets. Effects of Lp-PLA2 overexpression were studied in classical vs. intermediate and non-classical subsets. Results: The classical monocytes expressed the highest Lp-PLA2 mRNA levels as compared to other subpopulations. CKD5-D patients revealed significantly higher Lp-PLA2 transcripts, as well as higher Lp-PLA2 plasma activity as compared to healthy and “inflammatory” controls. In vitro data confirmed that uremia significantly contributes to Lp-PLA2 mRNA upregulation. Non-classical monocytes of A+ patients revealed significant higher Lp-PLA2 mRNA compared to A-. Conclusion: Uremic environment but not inflammation per se increases plasma Lp-PLA2 activity and upregulates monocytic Lp-PLA2 mRNA expression. The highest Lp-PLA2 levels were found in the classical and not in the inflammatory subsets. Atherosclerosis also contributes to a subset-specific increase in Lp-PLA2 mRNA expression.

Effects of dl‐3‐n‐butylphthalide on serum lipoprotein‐associated phospholipase A2 and hypersensitive C‐reactive protein levels in acute cerebral infarction

“…At present, it has been considered that (Alkuraishy et al, ; Yang et al, ) some kinds of Lp‐PLA2 that can bind with high density lipoprotein (HDL) can hydrolyze oxidized phospholipids in blood, reduce the accumulation of inflammatory mediators in phagocytes, and inhibit foam cell formation, thereby exerting anti‐inflammatory and anti‐atherosclerotic effects. In the process of the hydrolysis of oxidized low‐density lipoprotein (ox‐LDL), sLp‐PLA2 produces oxidized free fatty acids (ox‐FFA) and lysolecithin (lyso‐PC) (Bonnefont‐Rousselot, ; Ulrich et al, ). These two potent inflammatory substances damage endothelial cells and induce the expression of adhesion factors through oxidative stress and promote monocytes to aggregate into the lumen to form macrophages.…”

Differential expression of Lp-PLA2 in obesity and type 2 diabetes and the influence of lipids

“…Interestingly, relative to people without diabetes, there is a fourfold increase in intracellular Lp-PLA2 levels in adipose tissue from individuals with type 2 diabetes; this may, in part, explain the systemic changes in Lp-PLA2 plasma levels in type 2 diabetic individuals. It should also be noted that other cell types secrete Lp-PLA2, such as monocytes, macrophages, T lymphocytes and mast cells, providing an additional source of circulating Lp-PLA2 in type 2 diabetes [ 35 , 36 ].…”

Serum Level of Lipoprotein-Associated Phospholipase A2 and Coronary Artery Disease

“…This is in agreement with Caslake et al, [27] who demonstrated that LP-LPA2 levels were higher in 94 patients with CAD than in 54 controls. The connection remained even after controlling for LDL and HDL-cholesterol, smoking, and systolic blood pressure [28].…”