Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inappropriate platelet activation is a feature of acute and chronic diseases such as disseminated intravascular coagulation (DIC) and atherosclerosis. Since proinflammatory microbial-derived agonists can be involved in the pathogenesis of these diseases, we examined the potential role of TLR4 (mediating responses to LPS) and TLR2 (which responds to bacterial lipopeptides) in platelet activation. Our data suggested low-level expression of TLR2 and TLR4 on platelets, determined by flow cytometry, and we also observed expression of TLR4 on a megakaryocytic cell line by both flow cytometry and immunohistochemistry. Stimulation of the platelets with the TLR4 agonist LPS, and the synthetic TLR2 agonist Pam3CSK4, resulted in no platelet aggregation, no increase in CD62P surface expression and no increase in the cytosolic concentration of Ca2+. The TLR agonists were also unable to directly activate platelets primed with epinephrine, or pretreated with a low concentration of ADP or PAF. Pretreatment of platelets with LPS or Pam3CSK4 also failed to modulate the platelet response to submaximal concentrations of the classical platelet agonists ADP and PAF. We conclude that the TLR agonists LPS and Pam3CSK4 have no direct effect on platelet activation and that platelet TLRs may be a remnant from megakaryocytes. TLR2 and TLR4 agonists are thought to have a significant role in diseases such as atherosclerosis and DIC, but our research suggests that this is through a mechanism other than direct platelet activation or by modification of platelet responses to other agonists.
 ...
PMID:Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. 1627 Jun 39

Atherosclerosis as a chronic inflammatory disease resulting from the imbalance of the pro- and anti-inflammatory factors in the vessel wall. PAF and PAF-like oxidized phospholipids generated upon LDL oxidation in the intima of the arteries may interact with infiltrated monocytes/macrophages and lead to the alteration of gene expression patterns accompanied by an impaired production of chemokines, interleukins and proteolytic and lipolytic enzymes. The aim of this study was to evaluate the binding capacity of the major component of PAF-like oxidized phospholipids, namely the 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) to PAF-receptor (PAF-R) on the surface of human monocytes/macrophages and to further characterize the gene expression induced by such binding. We show that, POVPC binds to cultured human macrophages via PAF-R and transduces the signals leading to the intracellular Ca(2+) fluxes and modifies the transcription levels of numerous pro-inflammatory and pro-atherogenic genes. Although a some similarity of the gene expression patterns was observed when macrophages were activated with POVPC versus PAF, we observed that only POVPC treatment induced a several-fold activation of IL-8 gene. In turn, only PAF activated PAF-R, matrix metalloproteinase-13 and 15-lipoxygenase mRNA accumulation. Thus, we suggest, that POVPC signals in mature macrophages only in part through the PAF-R, a part of its effects may involve other receptors.
Atherosclerosis 2006 Oct
PMID:Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophages. Implications in atherosclerosis. 1638 58

Physical activity is known to play a cardioprotective role. Nevertheless, a paradox seems to arise when considering that aerobic exercise enhances oxidative stress. In previous works, we showed that free radical formation during physical activity was counteracted by an increase in antioxidant defenses. Low density lipoprotein (LDL) oxidation is a crucial step in atherosclerosis, process that can be inhibited by high density lipoprotein (HDL) through its oxidable components or associated enzymes like paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH). In this study, we evaluated copper-induced oxidation in isolated LDL and HDL fractions, and the effect of HDL on LDL oxidation in samples from well trained amateur athletes who were participating in an ultra-distance triathlon (n=18) in comparison with healthy sedentary controls (n=18). PON and PAF-AH activities and PON phenotype were also evaluated. The oxidability of isolated lipoproteins, as well as HDL antioxidant capacity, was similar in both groups of subjects. After classification by paraoxonase phenotype, only sportsmen belonging to the QR phenotype showed higher HDL susceptibility to in vitro oxidation (thiobarbituric reactive substances, TBARS) than controls (p<0.05). HDL oxidability exhibited a positive correlation with its triglyceride content (r=0.58; p<0.01). Similarly, HDL capacity to inhibit LDL oxidation was increased in athletes (p<0.05) which was positively associated with HDL oxidability (HDL-TBARS: r=0.55, p<0.005; HDL-lag time: r=0.45, p<0.01; HDL-D max: r=0.35, p<0.05). In conclusion, regular aerobic exercise was associated to a more efficient antioxidant function played by HDL from PON-QR carriers, which could constitute an adaptive response to the increased oxidative stress.
 ...
PMID:HDL capacity to inhibit LDL oxidation in well-trained triathletes. 1648 45

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been shown to play a crucial role in atherosclerosis, and has been proposed as a promising target for drug discovery. Here, we cloned the Lp-PLA(2) gene from differentiated THP-1 cells, and inserted a carboxy-terminal His(6)-tagged version of the gene into the pPIC9 Pichia expression vector. The Lp-PLA(2) fusion protein was successfully expressed in Pichia pastoris expression system and could be rapidly purified to apparent homogeneity using a single-step purification method. The activity of our recombinant Lp-PLA(2) was strong when [3H] PAF was used as a substrate, and the Lp-PLA(2) inhibitor SB435495 exhibited an inhibitory curve against the recombinant Lp-PLA2 (IC50 = 15.93 +/- 1 microM). This novel recombinant Lp-PLA(2) could prove useful as a screening model for Lp-PLA(2) inhibitors, and may facilitate further investigation of this protein in atherosclerosis.
 ...
PMID:Cloning, expression, and purification of lipoprotein-associated phospholipase A(2) in Pichia pastoris. 1669 Oct 4

The carotid intima-media thickness (IMT) can reflect early atherosclerosis. Oxidative modification of low-density lipoprotein (LDL) leads to the formation of several immunogenic epitopes and different forms of antibodies against oxidized LDL (oxLDL). We investigated the possible relationship between autoantibody titers against various forms of mildly oxLDL and carotid IMT in patients (n=100) with primary hyperlipidemia. Three different types of mildly oxidized LDL-oxLDL(L), oxLDL(P), and oxLDL(D)-were prepared at the end of lag, propagation, and decomposition phases of oxidation, respectively. Similar types of oxLDL were also prepared from the same LDL preparations after inactivation of the LDL-associated platelet-activating factor acetylhydrolase (PAF-AH). These types were denoted as oxLDL(-)(L), oxLDL(-)(P), and oxLDL(-)(D). OxLDL types are primarily enriched in lysophosphatidylcholine (lyso-PC) due to hydrolysis of oxidized phospholipids (oxPL) by PAF-AH. OxLDL(-) types are mainly enriched in intact oxPL due to the inactivation of the LDL-associated PAF-AH before oxidation. IgG autoantibodies against all types of oxLDL were determined and IMT was evaluated ultrasonographically. IMT values were significantly associated with age, systolic blood pressure and serum triglyceride levels, whereas no correlation was found between IMT values and antibody titers against all types of either oxLDL or oxLDL(-). We suggest that autoantibodies against various types of mildly oxidized LDL enriched either in lyso-PC or in oxPL are not associated with the extent of carotid atherosclerosis. This supports the concept that extensively oxidized LDL enriched in aldehydes rather than mildly oxidized LDL may play a prominent role in the early stage of atherosclerosis.
 ...
PMID:Antibodies against various forms of mildly oxidized low-density lipoprotein are not associated with carotid intima-media thickness in patients with primary hyperlipidemia. 1706 85

Lipoprotein-associated phospholipase (Lp-PL)A2 is a recently described and potentially useful plasma biomarker associated with cardiovascular disease. The enzyme, originally named platelet-activating factor acetylhydrolase (PAF-AH), has two prominent biological activities. First, it inactivates the prominent proinflammatory mediator PAF-AH. Second, Lp-PLA2 hydrolyzes oxidatively modified polyunsaturated fatty acids producing lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (OxNEFA). OxNEFA have potent monocyte chemotactic activity and LysoPC upregulates inflammatory mediators, including cytokines, adhesion molecules and the chemotactic mediator MCP-1. Whereas the first activity may be considered antiatherogenic, the prevailing consensus is that Lp-PLA2 is positively associated with coronary disease. Initial evidence for this came largely from the West of Scotland Coronary Prevention Study Group (WOSCOPS) in which Lp-PLA2 was compared among 580 cases and 1160 age-matched controls. In addition, the quantitative contribution of Lp-PLA2 to risk assessment was assessed in a substudy of the Atherosclerosis Risk in Communities (ARIC) study. Although positively correlated with disease, the addition of Lp-PLA2 did not appreciably enhance risk prediction beyond the model employing traditional risk factors. Thus, population screening for subclinical disease using Lp-PLA2 does not appear to be warranted. Presently, the most useful application of Lp-PLA2 testing is to adjust individual risk assessment for those patients found to be at borderline risk using traditional models. In this regard, the marker appears to be particularly useful for gauging risk among patients with metabolic syndrome or diabetes. There is observational evidence that Lp-PLA2 may be a useful guide for therapeutic efficacy, but prospective evaluation will be required. Considering the large number of biomarkers currently under evaluation, it is probable that useful additions to existing risk models may be found in combinatorial models.
 ...
PMID:Lipoprotein-associated phospholipase A2: a new biomarker for cardiovascular risk assessment and potential therapeutic target. 1789 60

Olive oil polar lipid (OOPL) extract has been reported to inhibit atherosclerosis development on rabbits. Olive pomace polar lipid (PPL) extract inhibits PAF activity in vitro and the most potent antagonist has been identified as a glycerylether-sn-2-acetyl glycolipid with common structural characteristics with the respective potent antagonist of OOPL. The aim of this study was to investigate the effect of PPL on early atherosclerosis development on rabbits and to compare it with the antiatherosclerotic effect of OOPL. OOPL and PPL inhibition potency, towards both PAF action and PAF binding, was tested in vitro on washed rabbit platelets. Consequently, rabbits were divided into three groups (A, B, and C). All groups were fed atherogenic diet for 22 days. Atherogenic diets in groups B and C were enriched with OOPL and PPL, respectively. At the end of the experimental time, rabbits were euthanized and aortic samples were examined histopathologically. OOPL and PPL inhibited PAF-induced aggregation, as well as specific PAF binding, with PPL being more potent. Free and bound PAF levels and PAF-AH activity were significantly elevated at the end of the experimental time. Plasma total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides levels were also found increased. Groups B and C exhibited significantly increased values of EC(50) compared to group A. Histopathological examination revealed that the development of early atherosclerosis lesions in groups B and C were significantly inhibited compared to group A. Significant differences were noted in the early atherosclerosis lesions between groups B and C, thus indicating that PPL exhibit its anti-atherosclerotic activity by blocking PAF receptor. Specific PAF antagonists with similar in vitro and in vivo bioactivity to those that have been previously reported in OOPL exist in PPL.
 ...
PMID:Antithrombotic and antiatherosclerotic properties of olive oil and olive pomace polar extracts in rabbits. 1825 66

Enhanced oxidative stress is implicated in the development of atherosclerosis in humans and animal models. F(2)-isoprostanes are formed in vivo via free radical peroxidation of arachidonic acid, and their quantification has allowed assessment of oxidative stress in vivo. F(2)-isoprostanes associate with lipids, although their distribution in human plasma lipoproteins is unknown. Our aim was to determine the distribution and levels of F(2)-isoprostanes in lipoproteins isolated from human plasma by ultracentrifugation and fast protein liquid chromatography (FPLC). F(2)-isoprostanes were significantly higher in HDL compared with LDL or VLDL after isolation by ultracentrifugation or FPLC. Furthermore, HDL3 particles contained elevated levels of F(2)-isoprostanes compared with HDL2. Platelet activating factor acetylhydrolase (PAF-AH), which hydrolyses esterified F(2)-isoprostanes from phospholipids, was predominantly associated with LDL. Reduced F(2)-isoprostanes in LDL may be related to higher PAF-AH activity in LDL. Paraoxonase 1 (PON-1) activity was associated with HDL2 and may be a contributing factor to the lower F(2)-isoprostanes in HDL2 compared with HDL3. Further studies are required to establish the implications of these findings on HDL function.
 ...
PMID:HDL is the major lipoprotein carrier of plasma F2-isoprostanes. 1914 35

The plasma form of the human enzyme platelet activating factor acetylhydrolase (PAF-AH) has been crystallized, and X-ray diffraction data were collected at a synchrotron source to a resolution of 1.47 A. The crystals belong to space group C2, with unit cell parameters of a = 116.18, b = 83.06, c = 96.71 A, and beta= 115.09 degrees and two molecules in the asymmetric unit. PAF-AH functions as a general anti-inflammatory scavenger by reducing the levels of the signaling molecule PAF. Additionally, the LDL bound enzyme has been linked to atherosclerosis due to its hydrolytic activities of pro-inflammatory agents, such as sn-2 oxidatively fragmented phospholipids.
 ...
PMID:Crystallization and preliminary X-ray crystallographic analysis of human plasma platelet activating factor acetylhydrolase. 1914 81

Phospholipases A2 (PLA2) are a family of enzymes that catalyze the hydrolysis of the sn-2 ester bond of glycerophospholipids liberating lysophospholipids and free fatty acids; important second messengers involved in atherogenesis. Plasma PAF-acetylhydrolase (PAF-AH) or Lp-PLA2 is a Ca(2+)-independent PLA2 which is produced by monocyte-derived macrophages and by activated platelets, and circulates in plasma associated with lipoproteins. PAF-AH catalyzes the removal of the acetyl/short acyl group at the sn-2 position of PAF and oxidized phospholipids produced during inflammation and oxidative stress. In humans, PAF-AH is mainly associated with small dense LDL and to a lesser extent with HDL and with lipoprotein(a). PAF-AH is N-glycosylated prior to secretion which diminishes its association with HDL raising the question of its distribution between the proatherogenic LDL vs the antiatherogenic HDL. Hypercholesterolemic patients have higher plasma PAF-AH activity which is reduced upon hypolipidemic therapy. PAF-AH specific inhibitor darapladib stabilizes human and swine plaques, therefore challenging the antiatherogenic potential of PAF-AH shown in small animal models. Among secreted PLA2s (sPLA2), the group X sPLA2 (PLA2GX), due to its very high activity towards phosphatidylcholine the main phospholipid of LDL, became an attractive target in atherosclerosis. We showed that PLA2GX is present in human atherosclerotic lesions and that the PLA2GX-phospholipolysed LDL triggers human macrophage-foam cell formation. In contrast to other sPLA2s, including group IB, IIA and V, PLA2GX can efficiently hydrolyze PAF present in lipoproteins or vesicles indicating that PLA2GX may be a novel player in PAF regulation upon inflammatory processes. By a genetic approach we uncovered a relatively rare polymorphism (Arg38Cys) which produces a catalytically inactive PLA2GX; although no association was observed with cardiovascular risk factors in the AtheroGene study, this result should be replicated in cohorts of other inflammatory diseases. We anticipate that mores studies will be necessary to sort out the exact role of extracellular PLA2 family members in atherosclerosis initiation and progression.
 ...
PMID:Extracellular phospholipases in atherosclerosis. 2015


<< Previous 1 2 3 4 5 6 7 Next >>