Lipoprotein-Associated Phospholipase A ₂ , Platelet-Activating Factor Acetylhydrolase, Is Expressed by Macrophages in Human and Rabbit Atherosclerotic Lesions

Abstract

Abstract-We studied the expression of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), an enzyme capable of hydrolyzing platelet-activating factor (PAF), PAF-like phospholipids, and polar-modified phosphatidylcholines, in human and rabbit atherosclerotic lesions. Oxidative modification of low-density lipoprotein, which plays an important role in atherogenesis, generates biologically active PAF-like modified phospholipid derivatives with polar fatty acid chains. PAF is known to have a potent proinflammatory activity and is inactivated by its hydrolysis. On the other hand, lysophosphatidylcholine and oxidized fatty acids released from oxidized low-density lipoprotein as a result of Lp-PLA 2 activity are thought to be involved in the progression of atherosclerosis. Using combined in situ hybridization and immunocytochemistry, we detected Lp-PLA 2 mRNA and protein in macrophages in both human and rabbit atherosclerotic lesions. Reverse transcriptase-polymerase chain reaction analysis indicated an increased expression of Lp-PLA 2 mRNA in human atherosclerotic lesions. In addition, Ϸ6-fold higher Lp-PLA 2 activity was detected in atherosclerotic aortas of Watanabe heritable hyperlipidemic rabbits compared with normal aortas from control rabbits. It is concluded that (1) macrophages in both human and rabbit atherosclerotic lesions express Lp-PLA 2 , which could cleave any oxidatively modified phosphatidylcholine present in the lesion area, and (2) modulation of Lp-PLA 2 activity could lead to antiatherogenic effects in the vessel wall.

Amelioration of atherosclerosis in apolipoprotein E-deficient mice by inhibition of lipoprotein-associated phospholipase A2

“…In addition, distinct temporal roles for Lp-PLA 2 during lesion pathogenesis cannot be ruled out. Lp-PLA 2 is upregulated in macrophages within vulnerable and ruptured plaques, but not within stable lesions [35,36]. As Lp-PLA 2 predominantly exists in advanced plaques, it may play an important role in advanced lesions and the determination of plaque instability, but not at earlier stages of atherogenesis.…”

Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein

“…Elevated expression of PAF-AH activity and/or protein has been reported in patients with coronary artery disease by a number of groups, and is thought to be an independent predictor of disease severity in humans (24 -33). In addition, PAF-AH protein has been detected in atherosclerotic plaques of humans (34,35) and in experimental animals (36). These correlative findings led to the proposition that PAF-AH actively contributes to the pathogenesis of vascular disease and that inhibiting its enzymatic activity could be beneficial for the treatment of atherosclerosis and related disorders (37)(38)(39).…”

Higher lipoprotein-associated phospholipase A2 levels are associated with coronary atherosclerosis documented by coronary angiography

“…Oxidized LDL (oxLDL) is a substrate in reactions catalysed by Lp-PLA2 that result in lysophosphatidylcholine (lysoPC) and oxidized fatty acid. 10,18,19 The progressive inactivation of Lp-PLA2 during LDL oxidation leads to increased oxLDL uptake by macrophages, which could be attributed primarily to the increased uptake of the oxidized phospholipid-enriched lipid moiety of oxLDL. 20 The oxidized phospholipids of oxLDL accumulate in atherosclerotic lesions and up-regulate Lp-PLA2 production.…”