Increased PAFAH and Oxidized Lipids Are Associated With Inflammation and Atherosclerosis in Hypercholesterolemic Pigs

Abstract

Objective-To study the association of PAF-acetyl hydrolase (PAFAH) activity with inflammation, oxidative stress, and atherosclerosis in hypercholesterolemic swine. Methods and Results-Cholesterol-rich diet feeding of miniature pigs was associated with an increase in PAFAH activity and an increase of the PAFAH to PON1 ratio. PLA2G7 RNA (coding for PAFAH) expression was increased in blood monocytes and plaque macrophages. Increased PAFAH activity was associated with higher plasma lysophosphatidylcholine and correlated with oxidized LDL. In THP1 monocytes and macrophages and in human blood-derived macrophages, oxidized LDL induced PLA2G7 RNA expression. Atherogenic diet feeding induced the accumulation of macrophages and oxidized LDL in the arterial wall leading to atherosclerosis. PAFAH activity correlated positively with plaque size and TNFalpha expression in plaque macrophages. Conclusions-We demonstrated that an increase in PAFAH activity was associated with increased levels of lysophosphatidylcholine, oxidized LDL, and inflammation, resulting in accelerated atherosclerosis in hypercholesterolemic minipigs. The significant correlation between PLA2G7 RNA expression in plaque macrophages and plasma PAFAH activity suggests that the latter is a consequence, rather than a cause of macrophage accumulation. Our cell experiments suggest that oxidized LDL can induce PAFAH, resulting in accumulation of lysophosphatidylcholine that increases the inflammatory action of oxidized LDL. Key Words: atherosclerosis Ⅲ oxidative stress Ⅲ inflammation Ⅲ PAFAH Ⅲ genes I t is clear that inflammation and oxidative stress are associated with cardiovascular diseases and underlying atherosclerosis. [1][2][3][4] Blood monocytes and plaque macrophages play a key role in the onset and development of the inflammatory reaction by generating bioactive molecules, such as platelet-activating-factor (PAF), in response to a variety of stimuli. 5,6 Oxidative stress is closely associated with the inflammatory response and bioactive lipid formation. Oxidation of LDL results in the formation of oxidized phospholipids and PAF-like molecules, which are potent bioactive lipids contributing to inflammation. 7 The uptake of oxidized LDL (oxLDL) by macrophages results in the formation of lipidloaded foam cells. In a later stage, macrophage-rich areas are more prone to disruption, leading to thrombus formation and consequently to acute coronary syndromes. 8 HDL, in contrast to oxLDL, protects against atherosclerosis because of its antiinflammatory and antioxidant properties. 9,10 HDL-associated paraoxonase-1 (PON1) is the primary enzyme responsible for the antiinflammatory and antioxidant activities of HDL. 11 Purified human PON1 decreases the accumulation of lipoperoxides in LDL thus preventing LDL oxidation. 12 In addition, PON1 reduces the ability of oxLDL to induce monocyte binding and transmigration and thereby inflammation in the vessel wall. 13 However, if PON1 fails to prevent the oxidation of LDL, oxidized phospholipids become substrate for platelet...

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

“…Increased Lp-PLA 2 mass in this setting may represent in vivo evidence for PAF-and/or OxPL-mediated effects on Lp-PLA 2 expression. De Keyzer and colleagues showed that a high-fat diet, which led to increased levels of oxidized LDL, was accompanied by robust increases in Lp-PLA 2 activity ( 55 ). When this response was modeled in a cellular system, the investigators found that oxidized LDL robustly increased expression of Lp-PLA 2 mRNA in THP1 cells and, to a lesser extent, human monocytederived macrophages ( 55 ).…”

“…De Keyzer and colleagues showed that a high-fat diet, which led to increased levels of oxidized LDL, was accompanied by robust increases in Lp-PLA 2 activity ( 55 ). When this response was modeled in a cellular system, the investigators found that oxidized LDL robustly increased expression of Lp-PLA 2 mRNA in THP1 cells and, to a lesser extent, human monocytederived macrophages ( 55 ). These combined results suggest that oxidized LDL, PAF, and perhaps OxPL upregulate expression of Lp-PLA 2 in vivo, possibly by increasing mRNA synthesis or stability, resulting in higher protein expression.…”

Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68

“…Recently, high levels of PLA2G7 activity were implicated in a swine model of coronary artery disease by increasing inflammation in the necrotic cores of atherosclerotic plaques (73). In this animal model, pharmacological inhibition of PLA2G7 reduced inflammation and disease severity by reducing levels of proinflammatory lysophosphatidylcholine (77).…”

Incorporating biomarkers into clinical trials in cardiovascular medicine

“…87,88 A recent study on hypercholesterolemic minipigs showed that elevated Lp-PLA 2 activity increased levels of lysophosphatidylcholine, oxidized LDL, and activity of proinflammatory genes in coronary plaque macrophages, which hasten the progression of atherosclerosis. 89 The suggestion of Lp-PLA 2 as a predictor for cardiovascular diseases originated from the West of Scotland Coronary Prevention Study (WOSCOPS) in which each of the 580 men presenting with a coronary event (ie, nonfatal MI, death from CHD, or a revascularization procedure) were matched for age and smoking status with two control subjects (1,160 controls in total) from the same cohort without a coronary event. 90 Lp-PLA 2 , CRP, and fibrinogen levels were measured at baseline along with other traditional risk factors.…”