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1.
Lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase) and cardiovascular disease 总被引:6,自引:0,他引:6
PURPOSE OF REVIEW: Plasma lipoproteins carry a number of highly active enzymes in the circulation. One of these is lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), also known as platelet-activating factor acetylhydrolase. This review addresses the molecular properties of Lp-PLA(2), the controversy surrounding its role in atherosclerosis and the regulation of its plasma levels in humans. RECENT FINDINGS: Recent reports indicate that the enzyme Lp-PLA(2) found in both LDL and HDL may be independently regulated in these lipoprotein subclasses and have distinct roles in atherogenesis. Seminal findings establishing the response-to-retention hypothesis of atherosclerosis support further the potentially damaging role that in-situ release of LDL-associated oxidative products by Lp-PLA(2) may have in the formation of arterial wall lesions. In the mouse, where Lp-PLA(2) circulates mainly bound to HDL, overexpression leads to reduced atherosclerosis, raising the possibility that the enzyme in HDL may have a protective role. Further evidence for a potential protective role is seen in studies of partial or complete deficiency of the enzyme. In the more general setting of population studies, however, it is clear that Lp-PLA(2) is a positive risk factor for coronary disease and measurements of its mass may contribute to the prediction of coronary heart disease risk, especially in individuals with low LDL cholesterol levels. SUMMARY: Lp-PLA(2) is an enzyme with potentially multiple risks in atherosclerosis. In humans the weight of evidence suggests that it is a positive risk factor for coronary heart disease - an observation commensurate with its position in the direct pathological sequence leading from formation of oxidized LDL in the artery wall to cellular dysfunction and formation of lesions. 相似文献
2.
The role of inflammation in atherosclerosis continues to emerge. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a novel plasma biomarker, circulates in the blood bound mainly to low-density lipoprotein (LDL) and promotes vascular inflammation. Several epidemiological studies have shown that circulating levels of Lp-PLA(2) are an independent risk factor for cardiovascular events. Recent studies demonstrate that Lp-PLA(2) is also associated with endothelial dysfunction and early atherosclerosis. This review provides an overview of these studies, suggests plausible mechanisms for the association between endothelial dysfunction and Lp-PLA(2), and highlights future potential therapies. 相似文献
3.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) plays important roles in both the inhibition and promotion of inflammation in human disease. It catalyzes the hydrolytic inactivation of plasma platelet activating factor (PAF) and is also known as PAF acetylhydrolase. High levels of PAF are implicated in a variety of inflammatory diseases such as asthma, necrotizing enterocolitis, and sepsis. Lp-PLA(2) also associates with lipoproteins in human plasma where it hydrolyzes oxidized phospholipids to produce pro-inflammatory lipid mediators that can promote inflammation and the development of atherosclerosis. Lp-PLA(2) plasma levels have recently been identified as a biomarker of vascular inflammation, atherosclerotic vulnerability, and future cardiovascular events. The enzyme is thus a prominent target for the development of inflammation and atherosclerosis-modulating therapeutics. While the crystallographically determined structure of the enzyme is known, the enzyme's mechanism of interaction with PAF and the function-modulating lipids in lipoproteins is unknown. We have employed peptide amide hydrogen-deuterium exchange mass spectrometry (DXMS) to characterize the association of Lp-PLA(2) with dimyristoylphosphatidylcholine (DMPC) vesicles and found that specific residues 113-120 in one of the enzyme's surface-disposed hydrophobic α-helices likely mediate liposome binding. 相似文献
4.
Wilensky RL Shi Y Mohler ER Hamamdzic D Burgert ME Li J Postle A Fenning RS Bollinger JG Hoffman BE Pelchovitz DJ Yang J Mirabile RC Webb CL Zhang L Zhang P Gelb MH Walker MC Zalewski A Macphee CH 《Nature medicine》2008,14(10):1059-1066
Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke. 相似文献
5.
Giuseppe Maiolino Luigi Pedon Maurizio Cesari Anna Chiara Frigo Robert L. Wolfert Marlena Barisa Leopoldo Pagliani Giacomo Rossitto Teresa Maria Seccia Mario Zanchetta Gian Paolo Rossi 《PloS one》2012,7(10)
Objective
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is deemed to play a role in atherosclerosis and plaque destabilization as demonstrated in animal models and in prospective clinical studies. However, most of the literature is either focused on high-risk, apparently healthy patients, or is based on cross sectional studies. Therefore, we tested the hypothesis that serum Lp-PLA2 mass and activity are useful for predicting cardiovascular (CV) events over the coronary atherosclerotic burden and conventional risk factors in high-risk coronary artery disease patients.Methods and Results
In a prospective cohort study of 712 Caucasian patients, who underwent coronary angiography and measurement of both Lp-PLA2 mass and activity at baseline, we determined incident CV events at follow-up after splitting the patients into a high and a low Lp-PLA2 mass and activity groups based on ROC analysis and Youden index. Kaplan-Meier and propensity score matching analysis were used to compare CV event-free survival between groups. Follow-up data were obtained in 75% of the cohort after a median of 7.2 years (range 1–12.7 years) during which 129 (25.5%) CV events were observed. The high Lp-PLA2 activity patients showed worse CV event-free survival (66.7% vs. 79.5%, p = 0.023) and acute coronary syndrome-free survival (75.4% vs. 85.6%, p = 0.04) than those in low Lp-PLA2 group.Conclusions
A high Lp-PLA2 activity implies a worse CV prognosis at long term follow up in high-risk Caucasian patients referred for coronary angiography. 相似文献6.
Heterologous expression of lipoprotein-associated phospholipase A2 in different expression systems 总被引:1,自引:0,他引:1
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a key enzyme involved in atherosclerosis, and has been considered as a new target for drug discovery. The major difficulty for high-throughput screening of Lp-PLA(2) inhibitors and for functional studies was their fast and efficient production. Purification of native Lp-PLA(2) from human plasma was complicated and produced a very low yield. We herein examined the feasibility of expressing and purifying recombinant Lp-PLA(2) in different heterologous expression systems. The fusion Lp-PLA(2) was expressed at high levels and exhibited strong enzyme activity in insect cell-baculovirus expression system. The functional enzyme could also be produced in Pichia pastoris. The inclusion of a Kozak sequence increased greatly the expression level of recombinant Lp-PLA(2) in insect cells, but had little effect on the expression of recombinant Lp-PLA(2) in P. pastoris and Escherichia coli. P. pastoris-produced Lp-PLA(2) could be purified rapidly and conveniently through a one-step procedure, while baculovirus-produced Lp-PLA(2) could be efficiently purified through a two-step procedure. This ability to readily produce recombinant Lp-PLA(2) could provide a screening model for Lp-PLA(2) inhibitors and will facilitate further studies on this enzyme. 相似文献
7.
In humans, a chronically increased circulating level of C-reactive protein (CRP), a positive acute-phase reactant, is an independent risk factor for cardiovascular disease. This observation has led to considerable interest in the role of inflammatory proteins in atherosclerosis. In this review, after discussing CRP, we focus on the potential role in the pathogenesis of human vascular disease of inflammation-induced proteins that are carried by lipoproteins. Serum amyloid A (SAA) is transported predominantly on HDL, and levels of this protein increase markedly during acute and chronic inflammation in both animals and humans. Increased SAA levels predict the risk of cardiovascular disease in humans. Recent animal studies support the proposal that SAA plays a role in atherogenesis. Evidence is accruing that secretory phospholipase A(2), an HDL-associated protein, and platelet-activating factor acetylhydrolase, a protein associated predominantly with LDL in humans and HDL in mice, might also play roles both as markers and mediators of human atherosclerosis. In contrast to positive acute-phase proteins, which increase in abundance during inflammation, negative acute-phase proteins have received less attention. Apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, decreases during inflammation. Recent studies also indicate that HDL is oxidized by myeloperoxidase in patients with established atherosclerosis. These alterations may limit the ability of apoA-I to participate in reverse cholesterol transport. Paraoxonase-1 (PON1), another HDL-associated protein, also decreases during inflammation. PON1 is atheroprotective in animal models of hypercholesterolemia. Controversy over its utility as a marker of human atherosclerosis may reflect the fact that enzyme activity rather than blood level (or genotype) is the major determinant of cardiovascular risk. Thus, multiple lipoprotein-associated proteins that change in concentration during acute and chronic inflammation may serve as markers of cardiovascular disease. In future studies, it will be important to determine whether these proteins play a causal role in atherogenesis. 相似文献
8.
Lipoprotein-associated phospholipase A2 as a target of therapy 总被引:7,自引:0,他引:7
PURPOSE OF REVIEW: Considerable discussion continues regarding the precise role that secreted lipoprotein-associated phospholipase A2 (Lp-PLA2), also called platelet-activating factor acetylhydrolase, plays in atherosclerosis. Since interest in this enzyme as a putative drug target has been based primarily upon its association with low-density lipoprotein (LDL) in human plasma, this review will focus on Lp-PLA2 and human coronary heart disease. RECENT FINDINGS: Recent reports have linked Lp-PLA2 enrichment not only to the most atherogenic of LDL particles but also to the most advanced, rupture-prone, plaques. Electronegative LDL has been shown to be highly enriched in Lp-PLA2; and in advanced atheroma, Lp-PLA2 levels are highly upregulated, colocalizing with macrophages in both the necrotic core and fibrous cap. Lp-PLA2 is well placed, whether on an oxidation susceptible LDL particle or in the highly oxidative environment of an advanced rupture-prone plaque, to hydrolyse oxidized phospholipid and generate significant quantities of the two pro-inflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acid. Several studies have confirmed that Lp-PLA2 is an independent risk factor for cardiovascular events (i.e. myocardial infarction and stroke). Although epidemiology studies consistently support a relationship between plasma Lp-PLA2 levels and susceptibility to coronary heart disease this is not the case for Lp-PLA2 polymorphisms. Two clinical studies have linked the Ala-379-->Val polymorphism with a reduced risk of myocardial infarction, but functional differences between the AA and VV polymorphs have yet to be demonstrated. SUMMARY: Lp-PLA2 is intimately associated with several aspects of human atherogenesis. Although various lipid-lowering therapies, such as statins, have been shown to reduce plasma levels of Lp-PLA2, none has been studied in terms of its ability to lower the large macrophage-mediated upregulation of Lp-PLA2 within advanced plaques. 相似文献
9.
Davis B Koster G Douet LJ Scigelova M Woffendin G Ward JM Smith A Humphries J Burnand KG Macphee CH Postle AD 《The Journal of biological chemistry》2008,283(10):6428-6437
There is increasing evidence that modified phospholipid products of low density lipoprotein (LDL) oxidation mediate inflammatory processes within vulnerable atherosclerotic lesions. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is present in vulnerable plaque regions where it acts on phospholipid oxidation products to generate the pro-inflammatory lysophsopholipids and oxidized non-esterified fatty acids. This association together with identification of circulating Lp-PLA(2) levels as an independent predictor of cardiovascular disease provides a rationale for development of Lp-PLA(2) inhibitors as therapy for atherosclerosis. Here we report a systematic analysis of the effects of in vitro oxidation in the absence and presence of an Lp-PLA(2) inhibitor on the phosphatidylcholine (PC) composition of human LDL. Mass spectrometry identifies three classes of PC whose concentration is significantly enhanced during LDL oxidation. Of these, a series of molecules, represented by peaks in the m/z range 594-666 and identified as truncated PC oxidation products by accurate mass measurements using an LTQ Orbitrap mass spectrometer, are the predominant substrates for Lp-PLA(2). A second series of oxidation products, represented by peaks in the m/z range 746-830 and identified by LTQ Orbitrap analysis as non-truncated oxidized PCs, are quantitatively more abundant but are less efficient Lp-PLA(2) substrates. The major PC products of Lp-PLA(2), saturated and mono-unsaturated lyso-PC, constitute the third class. Mass spectrometric analysis confirms the presence of many of these PCs within human atherosclerotic lesions, suggesting that they could potentially be used as in vivo markers of atherosclerotic disease progression and response to Lp-PLA(2) inhibitor therapy. 相似文献
10.
Ringseis R Müller A Herter C Gahler S Steinhart H Eder K 《Biochimica et biophysica acta》2006,1760(2):290-300
Conjugated linoleic acids (CLAs) were reported to have anti-atherogenic properties in animal feeding experiments. In an attempt to elucidate the molecular mechanisms of these anti-atherogenic effects, the modulatory potential of CLA on cytokine-induced eicosanoid production from smooth muscle cells (SMCs), which contributes to the chronic inflammatory response associated with atherosclerosis, has been investigated in the present study. cis-9, trans-11 CLA and trans-10, cis-12 CLA were shown to reduce proportions of the eicosanoid precursor arachidonic acid in SMC total lipids and to inhibit cytokine-induced NF-kappaB DNA-binding activity, mRNA levels of inducible enzymes involved in eicosanoid formation (cPLA2, COX-2, mPGES), and the production of the prostaglandins PGE2 and PGI2 by TNFalpha-stimulated SMCs in a dose-dependent manner. The effect of 50 micromol/L of either CLA isomer was as effective as 10 micromol/L of the PPARgamma agonist troglitazone in terms of inhibiting the TNFalpha-stimulated eicosanoid production by SMCs. PPARgamma DNA-binding activity was increased by both CLA isomers compared to control cells. Moreover, it was shown that the PPARgamma antagonist T0070907 partially abrogated the inhibitory action of CLA isomers on cytokine-induced eicosanoid production and NF-kappaB DNA-binding activity by vascular SMCs suggesting that PPARgamma signalling is at least partially involved in the action of CLA in human vascular SMCs. With respect to the effects of CLA on experimental atherosclerosis, our findings suggest that the anti-inflammatory effect of CLA is at least partially responsible for the anti-atherogenic effects of CLA observed in vivo. 相似文献
11.
Turunen P Jalkanen J Heikura T Puhakka H Karppi J Nyyssönen K Ylä-Herttuala S 《Journal of lipid research》2004,45(9):1633-1639
Oxidation of LDL generates biologically active platelet-activating factor (PAF)-like phospholipid derivatives, which have potent proinflammatory activity. These products are inactivated by lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme capable of hydrolyzing PAF-like phospholipids. In this study, we generated an adenovirus (Ad) encoding human Lp-PLA2 and injected 10(8), 10(9), and 10(10) plaque-forming unit doses of Adlp-PLA2 and control AdlacZ intra-arterially into rabbits to achieve overexpression of Lp-PLA2 in liver and in vivo production of Lp-PLA2-enriched LDL. As a result, LDL particles with 3-fold increased Lp-PLA2 activity were produced with the highest virus dose. Increased Lp-PLA2 activity in LDL particles decreased the degradation rate in RAW 264 macrophages after standard in vitro oxidation to 60-80% compared with LDL isolated from LacZ-transduced control rabbits. The decrease was proportional to the virus dose and Lp-PLA2 activity. Lipid accumulation and foam cell formation in RAW 264 macrophages were also decreased when incubated with oxidized LDL containing the highest Lp-PLA2 activity. Inhibition of the Lp-PLA2 activity in the LDL particles led to an increase in lipid accumulation and foam cell formation. It is concluded that increased Lp-PLA2 activity in LDL attenuates foam cell formation and decreases LDL oxidation and subsequent degradation in macrophages. 相似文献
12.
Chen CH 《Current opinion in lipidology》2004,15(3):337-341
PURPOSE OF REVIEW: Although findings obtained from various studies are inconclusive in determining whether plasma platelet-activating factor acetylhydrolase, or lipoprotein-associated phospholipase A2, plays a proatherogenic or antiatherogenic role in atherosclerosis, many recent reviews appear to favor it as a risk factor for coronary artery disease. To provide a contrasting view, this review focuses on the enzyme's antiatherogenic and antiinflammatory properties. RECENT FINDINGS: A recent report demonstrates that plasma platelet-activating factor acetylhydrolase activity increases in men and women with stable angina or acute coronary syndromes, supporting previously published data that plasma levels of the protein are independently and positively associated with the risk of coronary artery disease. In contrast, at least four lines of evidence indicate that the enzyme has strong antiatherogenic properties: (1) it inhibits the effects of LDL oxidation, (2) genetic deficiency of plasma levels constitutes a risk factor for vascular diseases including atherosclerosis, (3) adenoviral transfer of the protein reduces atherosclerosis in apolipoprotein E-deficient mice, and (4) pretreatment of an electronegative LDL subfraction isolated from hypercholesterolemic human plasma with a recombinant platelet-activating factor acetylhydrolase completely abolishes the proapoptotic effects of the electronegative LDL on vascular endothelial cells. Additionally, treatment with the recombinant product reduced mortality from severe sepsis in a phase IIb clinical trial. In an animal study, transfection of tumor cells with platelet-activating factor acetylhydrolase inhibited tumor growth at the site of implantation. SUMMARY: Plasma platelet-activating factor acetylhydrolase becomes progressively activated as atherosclerosis progresses, but lines of evidence indicate that the enzyme possesses potent antiatherogenic and antiinflammatory properties. This raises the question of whether increased activity is a cause or a result of atherosclerosis and, consequently, whether inhibiting the enzyme's activities may decelerate or accelerate the progress of the disease. 相似文献
13.
Plasma Platelet-activating-Factor (PAF)-acetylhydrolase (PAF-AH also named lipoprotein-PLA(2) or PLA(2)G7 gene) is secreted by macrophages, it degrades PAF and oxidation products of phosphatidylcholine produced upon LDL oxidation and/or oxidative stress, and thus is considered as a potentially anti-inflammatory enzyme. Cloning of PAF-AH has sustained tremendous promises towards the use of PAF-AH recombinant protein in clinical situations. The reason for that stems from the numerous animal models of inflammation, atherosclerosis or sepsis, where raising the levels of circulating PAF-AH either through recombinant protein infusion or through the adenoviral gene transfer showed to be beneficial. Unfortunately, neither in human asthma nor in sepsis the recombinant PAF-AH showed sufficient efficacy. One of the most challenging questions nowadays is as to whether PAF-AH is pro- or anti-atherogenic in humans, as PAF-AH may possess a dual pro- and anti-inflammatory role, depending on the concentration and the availability of potential substrates. It is equally possible that the plasma level of PAF-AH is a diagnostic marker of ongoing atherosclerosis. 相似文献
14.
Hepatic lipase: a pro- or anti-atherogenic protein? 总被引:15,自引:0,他引:15
Hepatic lipase (HL) plays a role in the metabolism of pro- and anti-atherogenic lipoproteins affecting their plasma level and composition. However, there is controversy regarding whether HL accelerates or retards atherosclerosis. Its effects on different lipoprotein classes show that, potentially, HL may promote as well as decrease atherogenesis. Studies in animals with genetically modulated HL expression show that it depends on the model used whether HL acts pro- or anti-atherogenic. In humans, HL activity seems to correlate inversely with atherosclerosis in (familial) hypercholesterolemia, and positively in hypertriglyceridemia. In normolipidemia, HL activity is weakly associated with coronary artery disease (CAD). Genetically low or absent HL activity is usually associated with increased CAD risk, especially if plasma lipid transport is impaired due to other factors. Since HL promotes the uptake of lipoproteins and lipoprotein-associated lipids, HL may affect intracellular lipid content. We hypothesize that the prime role of HL is to maintain, in concert with other factors (e.g., lipoprotein receptors), intracellular lipid homeostasis. This, and the uncertainties about its impact on human atherosclerosis, makes it difficult to predict whether HL is a suitable target for intervention to lower CAD risk. First, the physiological meaning of changes in HL activity under different conditions should be clarified. 相似文献
15.
Ringseis R Müller A Düsterloh K Schleser S Eder K Steinhart H 《Biochimica et biophysica acta》2006,1761(3):377-383
Conjugated linoleic acids (CLAs) are bioactive lipid compounds showing anti-atherogenic actions in cell culture experiments and animal models of atherosclerosis without exact knowledge about the underlying mechanisms. CLAs were recently reported to be further metabolized to bioactive conjugated metabolites indicating that these metabolites are possibly involved in mediating the anti-atherogenic actions of CLA. Regarding the lack of information with respect to the formation of CLA metabolites in the vascular endothelium, which is strongly involved in the process of atherosclerosis, the present study aimed to explore the potential formation of CLA metabolites in vascular endothelial cells. The results from the present study show for the first time that the CLA isomers cis-9, trans-11 CLA and trans-10, cis-12 CLA are metabolized within endothelial cells to beta-oxidation products such as CD16:2c7t9 and CD16:2t8c10 and elongation products such as CD20:2c11t13, CD20:2t12c14 as well as CD22:2c13t15 and CD22:2t14c16. Different CD16:2/CLA ratios observed between cells treated with different CLA isomers indicate that the metabolism of CLAs depends on the configuration of the conjugated double bonds. In conclusion, regarding the biological activity reported for CD20:2t12c14 and other metabolites of CLA, the present results indicate that metabolites of CLA are possibly also involved in mediating the anti-atherogenic actions of CLA. 相似文献
16.
Although an atherogenic lipoprotein phenotype has been well recognized as an important predictor of cardiovascular disease, recent studies have demonstrated a number of additional lipid-related markers as emerging biomarkers to identify patients at risk for future coronary heart disease. Among them, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), seems to be a promising candidate that might be added to the clinical armamentarium for improved prediction of cardiovascular disease in the future. Of particular note, Lp-PLA(2) is the only enzyme that cleaves oxidized low-density lipoprotein (oxLDL) in the subendothelial space, with further generation of proinflammatory mediators such as lysophosphatidylcholine (LysoPC) and oxidized fatty acid (oxFA), thereby probably linking two important features of atherogenesis, namely oxidation of LDL and local inflammatory processes within the atherosclerotic plaque. This overview aims to summarize our current knowledge based on observations from recent experimental and clinical studies. Emphasis has been put on potential pathophysiological mechanisms of action and on the clinical relevance of Lp-PLA(2) in a wide variety of clinical settings, including apparently healthy individuals, patients with stable angina or acute coronary syndromes, after myocardial infarction, and with subclinical disease. Although a growing body of evidence from epidemiological and clinical studies suggests that Lp-PLA(2) may represent an independent and clinically relevant long-term risk marker for coronary heart disease and, probably, also for stroke, the role of this enzyme in the setting of the acute coronary syndrome remains to be established. 相似文献
17.
Robert Ringseis André Müller Christian Herter Susan Gahler Hans Steinhart Klaus Eder 《Biochimica et Biophysica Acta (BBA)/General Subjects》2006
Conjugated linoleic acids (CLAs) were reported to have anti-atherogenic properties in animal feeding experiments. In an attempt to elucidate the molecular mechanisms of these anti-atherogenic effects, the modulatory potential of CLA on cytokine-induced eicosanoid production from smooth muscle cells (SMCs), which contributes to the chronic inflammatory response associated with atherosclerosis, has been investigated in the present study. cis-9, trans-11 CLA and trans-10, cis-12 CLA were shown to reduce proportions of the eicosanoid precursor arachidonic acid in SMC total lipids and to inhibit cytokine-induced NF-κB DNA-binding activity, mRNA levels of inducible enzymes involved in eicosanoid formation (cPLA2, COX-2, mPGES), and the production of the prostaglandins PGE2 and PGI2 by TNFα-stimulated SMCs in a dose-dependent manner. The effect of 50 μmol/L of either CLA isomer was as effective as 10 μmol/L of the PPARγ agonist troglitazone in terms of inhibiting the TNFα-stimulated eicosanoid production by SMCs. PPARγ DNA-binding activity was increased by both CLA isomers compared to control cells. Moreover, it was shown that the PPARγ antagonist T0070907 partially abrogated the inhibitory action of CLA isomers on cytokine-induced eicosanoid production and NF-κB DNA-binding activity by vascular SMCs suggesting that PPARγ signalling is at least partially involved in the action of CLA in human vascular SMCs. With respect to the effects of CLA on experimental atherosclerosis, our findings suggest that the anti-inflammatory effect of CLA is at least partially responsible for the anti-atherogenic effects of CLA observed in vivo. 相似文献
18.
Arai K Orsoni A Mallat Z Tedgui A Witztum JL Bruckert E Tselepis AD Chapman MJ Tsimikas S 《Journal of lipid research》2012,53(8):1670-1678
We measured oxidized phospholipids (OxPL), lipoprotein (a) [Lp(a)], and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) pre- and postapheresis in 18 patients with familial hypercholesterolemia (FH) and with low(~10 mg/dl; range 10-11 mg/dl), intermediate (~50 mg/dl; range 30-61 mg/dl), or high (>100 mg/dl; range 78-128 mg/dl) Lp(a) levels. By using enzymatic and immunoassays, the content of OxPL and Lp-PLA(2) mass and activity were quantitated in lipoprotein density fractions plated in microtiter wells, as well as directly on apoB-100, Lp(a), and apoA-I immunocaptured within each fraction (i.e., OxPL/apoB and Lp-PLA(2)/apoB). In whole fractions, OxPL was primarily detected in the Lp(a)-containing fractions, whereas Lp-PLA(2) was primarily detected in the small, dense LDL and light Lp(a) range. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apoB and Lp-PLA(2)/apoA-I levels were highest in the low Lp(a) group but decreased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apo(a) was lowest in patients with low Lp(a) levels and increased proportionally with increasing Lp(a) levels. Apheresis significantly reduced levels of OxPL and Lp-PLA(2) on apoB and Lp(a) (50-75%), particularly in patients with intermediate and high Lp(a) levels. In contrast, apheresis increased Lp-PLA(2)-specific activity (activity/mass ratio) in buoyant LDL fractions. The impact of apheresis on Lp(a), OxPL, and Lp-PLA(2) provides insights into its therapeutic benefits beyond lowering apoB-containing lipoproteins. 相似文献
19.
Ming Yang Eugene M. Chu Muriel J. Caslake Celina Edelstein Angelo M. Scanu John S. Hill 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2010,1801(2):176-182
We investigated whether the presence of endogenous or exogenous lipoprotein-associated phospholipase A2 (Lp-PLA2) can modify the cellular association of oxidized low density lipoprotein (oxLDL) and oxidized lipoprotein(a) (oxLp(a)) by human monocyte-derived macrophages (MDM) and hepatocytes (HepG2). Purified recombinant Lp-PLA2 was used as a source of exogenous enzyme whereas Pefabloc (serine esterase inhibitor) was used to inhibit the endogenous Lp-PLA2 activity associated with isolated lipoproteins. Cellular association studies were performed with DiI-labeled oxLDL or oxLp(a) and human monocyte-derived macrophages and HepG2 cells. Active Lp-PLA2 decreased the cellular association of oxLDL and oxLp(a) in macrophages and HepG2 cells by approximately 30–40%, whereas the inactive enzyme did not significantly change oxidized lipoprotein cellular association by either cell type. OxLDL pretreated by Pefabloc increased oxLDL cellular association by MDM and HepG2 cells compared to untreated oxLDL. Therefore, unlike some lipases, Lp-PLA2 did not appear to have any catalytic independent function in oxLDL cellular association. To assess whether the reduced cellular association mediated by Lp-PLA2 was due to the hydrolysis of oxidized phosphatidylcholine (oxPC), we measured the concentration of lysophosphatidylcholine (lysoPC) in lipoprotein fractions after Lp-PLA2 treatment. LysoPC was increased by 20% (0.4 μM) and 87% (0.7 μM) by active Lp-PLA2 compared to inactive Lp-PLA2 for oxLDL and Lp(a), respectively. LysoPC at higher concentration dose-dependently increased the cellular association of oxLDL and oxLp(a) in MDM and HepG2 cells. We conclude that Lp-PLA2 mediates a decrease in oxidized lipoprotein cellular association in human macrophages and HepG2 cells by reducing the concentration of oxPC within these lipoproteins. 相似文献
20.
Obesity, adiponectin and vascular inflammatory disease 总被引:28,自引:0,他引:28
PURPOSE OF REVIEW: Obesity is the most common risk factor for cardiovascular diseases in industrial countries. It is now clear that adipose tissue secretes various bioactive substances, conceptualized as adipocytokines, and that dysregulation of adipocytokines directly contributes to obesity-related diseases. Chronic inflammatory processes contribute to the development of atherosclerosis. In this review, the authors focus on the relationship between adiponectin, a recently discovered anti-atherogenic adipocytokine, and vascular inflammation. RECENT FINDINGS: Plasma concentrations of adiponectin, an adipocyte-specific protein, are reduced in obese subjects and in patients with type 2 diabetes and coronary artery disease. Adiponectin inhibits the expression of tumor necrosis factor-alpha-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-alpha expression in macrophages and adipose tissues, and smooth muscle cell proliferation. In addition, adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin-deficient mice exhibit an excessive vascular remodeling response to injury. Clinically, hypoadiponectinemia is closely associated with increased levels of inflammatory markers such as C-reactive protein and interleukin-6. SUMMARY: Adiponectin acts as an anti-inflammatory and anti-atherogenic plasma protein. Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease. 相似文献