Enhanced Expression of Lp-PLA ₂ and Lysophosphatidylcholine in Symptomatic Carotid Atherosclerotic Plaques

Abstract

Background and Purpose-Circulating lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) has emerged as a novel biomarker for cardiovascular diseases. However, the correlation between the plaque expression of Lp-PLA 2 and plaque oxidative stress, inflammation, and stability as well as the clinical presentation remains poorly defined, especially for cerebrovascular disease. Therefore, this study was performed to test the hypothesis that Lp-PLA 2 expression is higher in symptomatic than in asymptomatic carotid plaques of patients undergoing carotid endarterectomy. Methods-The expression of Lp-PLA 2 in 167 carotid artery plaques was determined by immunoblotting and immunostaining. Plaque oxidative stress, inflammation, and stability were quantified by NAD(P)H oxidase p67phox and MMP-2 immunoblotting, oxidized LDL (oxLDL) immunoreactivity, macrophage and Sirius red collagen staining. Lysophosphatidylcholine 16:0 (lysoPC) concentration was measured in 55 plaques using liquid chromatography tandem mass spectrometry. Results-Lp-PLA 2 expression was significantly higher in plaques of symptomatic patients than asymptomatic patients (1.66Ϯ0.19 versus 1.14Ϯ0.10, PϽ0.05) and localized mainly to shoulder and necrotic lipid core areas in colocalization with oxLDL and macrophage content. Similarly, Lp-PLA 2 expression was related to collagen content, which was lower in plaques from symptomatic patients than in plaques from asymptomatic patients (9.1Ϯ2.2 versus 18.5Ϯ1.7% of staining/field, PϽ0.001). LysoPC plaque concentration was significantly higher in plaques of symptomatic than asymptomatic patients (437.0Ϯ57.91 versus 228.84Ϯ37.00 mmol/L, PϽ0.05). Conclusions-Symptomatic carotid artery plaques are characterized by increased levels of Lp-PLA 2 and its product lysoPC in correlation with markers of tissue oxidative stress, inflammation, and instability. These findings strongly support a role for Lp-PLA2 in the pathophysiology and clinical presentation of cerebrovascular disease.

Lipoprotein-Associated Phospholipase A 2 and C-Reactive Protein for Risk-Stratification of Patients With TIA

“…A recent analysis of plaque specimens obtained after carotid endarterectomy demonstrated increased Lp-PLA 2 expression in patients with recent TIA or stroke compared to asymptomatic patients, and a correlation between Lp-PLA 2 content and markers of oxidative stress, inflammation and instability. 3 The results of our study provide further support for the role of Lp-PLA 2 as a biomarker of unstable atherosclerotic plaque. Both Lp-PLA 2 mass and activity were significantly associated with symptomatic Ͼ50% large vessel stenosis, but not with cardioembolism, consistent with a specific role in atherosclerotic disease.…”

“…Lipoproteinassociated phospholipase A 2 (Lp-PLA 2 ) and C-reactive protein are 2 candidate markers which have been associated with inflammation and plaque instability in histopathologic studies of the carotid arteries. 3,4 The primary aims of this study were to determine whether measurement of LpPLA 2 and highsensitivity C-reactive protein (CRP) could improve riskstratification of patients with TIA and to examine the relationship between these blood markers and TIA mechanism.…”

Link between Lipoprotein-Associated Phospholipase A₂ Gene Expression of Peripheral-Blood Mononuclear Cells and Prognostic Outcome after Acute Ischemic Stroke

“…For each isolation, 90 μL DNase incubation buffer was pipetted into a sterile 1.5 μL reaction tube, 10 μ of DNase I working solution was then added, factors, many inflammatory biomarkers in blood or damaged atherosclerotic plaque are useful for assessing the potential risk of cardiovascular diseases, monitoring disease propagation, and predicting the outcome in various clinical settings [1][2][3][4][5][6][7][8][9][10] . Of these biomarkers [1][2][3][4][5][6][7][8][9][10] , lipoprotein-associated phospholipase A2 (Lp-PLA2) has recently been described as a novel biomarker which is strongly associated with atherosclerosis-related inflammatory processes and plaque instability in histopathologic studies of the coronary and carotid arteries [10][11][12] . Lp-PLA2, also known as platelet-activating factor acetylhydrolase, is produced predominantly by monocyte-derived macrophages, T-lymphocytes and mast cells [13][14][15] .…”

“…(Table 3) The logistic regression test revealed that older age ( ≥ 65 years old), diabetes mellitus (DM), a positive past history of significant coronary artery obstruction treated by percutaneous coronary intervention (PCI) and the presence of significant ECCA stenosis were strongly associated with elevated Lp-PLA2 mRNA expression of PBMNCs. factor which may promote the generation of oxidized LDL-C and free fatty acid with subsequent direct participation in the formation and rupture of carotid plaques 10,12,15,18,19) . Our results also revealed a strong association between significant coronary artery or ECCA stenosis and elevated Lp-PLA2 mRNA expression of PBMNCs.…”

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

“…The macrophage foam cells generate reactive oxygen species (ROS), produce TNF-α and IL-1, and MMP-9 that promote atherosclerosis, degrade the fibrous cap, and eventually lead to plaque rupture [14]. Recent studies also showed that carotid atherosclerotic plaques from patients symptomatic of stroke had higher expression of lipoprotein-phospholipase A 2 (Lp-PLA 2 )/PAF acetylhydrolase, lyso-PC, OxLDL, macrophage content and MMP-2 compared to carotid plaques from asymptomatic patients [15].…”