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

In seeking an explanation of the inverse relationship between serum high density lipoprotein (HDL) concentration and coronary heart disease (CHD) incidence, most investigations have been directed at its role in reverse cholesterol transport. However, recently it has become clear that HDL has the potential to limit oxidative modification of low density lipoprotein (LDL) whether induced by transition metals or by cells in tissue culture. In view of the current theory that oxidative modification of LDL is an important element in atherogenesis, this suggests another potential mechanism by which HDL might impede the development of CHD. HDL is the major carrier of cholesteryl ester hydroperoxides, but more than this it appears to have the prolonged capacity to decrease the total amount of lipid peroxides generated on LDL during oxidation while the quantity accumulating on HDL itself reaches an early plateau. These effects are not explained by chain-breaking antioxidants present in HDL and are likely to involve an enzymic mechanism. Several enzymes are present on HDL: paraoxonase, lecithin:cholesterol acyl transferase, platelet activating factor acetylhydrolase, phospholipase D and protease. Apolipoproteins, such as apolipoprotein AI, could also have enzymic activity. Evidence that some of these might act to metabolise lipid peroxidation products, such as oxidised phospholipids and lyso-phosphatidylcholine, is discussed in this review.
Atherosclerosis 1995 Jun
PMID:HDL, its enzymes and its potential to influence lipid peroxidation. 766 83

Human plasma platelet activating factor acetylhydrolase (PAF-AH) is an enzyme associated mainly with the apolipoprotein B (apoB)-containing lipoproteins and primarily with low-density lipoprotein (LDL). A small proportion of enzyme activity is also associated with high-density lipoprotein (HDL). PAF-AH activity is essential for the metabolism of PAF and oxidized phospholipids, i.e. bioactive lipids that are involved in the pathophysiology of atherosclerosis. Thus, PAF-AH may play a significant role in atherogenesis. Accumulating data indicate that PAF-AH associated with HDL particles plays a predominantly antiatherogenic role. By contrast, the role of LDL-associated PAF-AH remains controversial. Dyslipidemia induces a significant increase in total plasma PAF-AH activity and alters the enzyme distribution between proatherogenic apoB- and antiatherogenic apo AI-containing lipoproteins by increasing the PAF-AH activity associated with apoB-containing lipoproteins. The decreased rate of LDL removal from the circulation and the abnormal catabolism of triglyceride-rich lipoproteins play important roles in these abnormalities. Atorvastatin or fenofibrate therapy can restore, at least partially, the dyslipidemia-induced alterations in plasma PAF-AH by increasing the ratio of HDL-PAF-AH to plasma PAF-AH (or to LDL-cholesterol) levels, which may represent an important antiatherogenic effect of these hypolipidemic drugs.
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PMID:Effect of hypolipidemic drugs on lipoprotein-associated platelet activating factor acetylhydrolase. Implication for atherosclerosis. 1460 31

Lipoprotein(a) [Lp(a)] may be an independent risk factor for coronary artery disease (CAD). Lp(a) is enriched in platelet activating factor acetylhydrolase (PAF-AH), an enzyme which hydrolyzes and inactivates platelet activating factor (PAF) and oxidized phospholipids that are implicated in atherogenesis. We determined the mass and catalytic properties of the Lp(a)-associated PAF-AH in 28 CAD patients in relation to the LDL-associated enzyme ones. Results were then compared to those of 30 control subjects and 16 unrelated patients with primary hypercholesterolemia (Type IIA dyslipidemia) before and after atorvastatin therapy. The mass, the specific activity and kinetic constants of the Lp(a)-associated PAF-AH were significantly lower in CAD patients compared to those of either controls or hypercholesterolemic patients, a phenomenon not observed for LDL-associated PAF-AH. The enzyme specific activity and kinetic constants were significantly increased after removal of apo(a) from Lp(a) by reductive cleavage, which was not found in the control population, suggesting that the apo(a) moiety of Lp(a) from CAD patients may play an important role in the observed lower catalytic efficiency of PAF-AH. The reduced PAF-AH mass and specific activity on Lp(a) is a feature characteristic of this lipoprotein in CAD patients and may lead to a diminished capability of Lp(a) to degrade proinflammatory phospholipids. The consequences of this phenomenon as regards the pathophysiological role of Lp(a) in atherosclerosis remain to be established.
Atherosclerosis 2004 Nov
PMID:Reduced PAF-acetylhydrolase activity associated with Lp(a) in patients with coronary artery disease. 1548 84

Phospholipases have received wide attention as it has become clear that several isoforms of the phospholipase family play a role in onset and progression of atherosclerosis. The release of free fatty acids (FFA) and lysophospholipids (lysoPL) provide metabolites for various inflammatory pathways, and this has been considered the main mechanism of phospholipase-driven inflammation. However, generation of FFA and lysoPL are only part of the story. The induction of low-density phospholipoprotein (LDL) aggregation and accumulation, receptor binding, co-regulation with cyclooxygenase (COX) and lip-oxygenase (LO) pathways, internalization through heparan sulfate proteoglycan (HSPG) shuttling, and crosstalk between phospholipases all play a role in atherosclerosis.Group IIA phospholipase has long been considered a key enzyme in the initiation of various inflammatory diseases, but new data also indicate a role in the subsequent resolution of inflammatory processes. Recently, secreted group V and group X phospholipase and platelet activating factor acetylhydrolase (PAF-AH) are also recognized as important enzymes in atherosclerosis, modifying LDL and leading to lipid accumulation. The phospholipases and their function in atherosclerosis are not fully under-stood. Future investigations can deliver better insight in the complex role of these enzymes. The present review summarizes the current state of phospholipase research related to atherosclerosis.
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PMID:The role of phospholipases in lipid modification and atherosclerosis. 1604 92

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and increased mortality from cardiovascular disease. CKD results in oxidative stress, inflammation, and high-density lipoprotein (HDL) deficiency, which work in concert to promote atherosclerosis. Normal HDL confers protection against atherosclerosis by inhibiting the oxidation of lipids and lipoproteins and by retrieving surplus cholesterol and phospholipids from lipid-laden cells in the artery wall for disposal in the liver (reverse cholesterol transport). The plasma level of oxidized low-density lipoprotein (LDL) is increased, plasma HDL-cholesterol is reduced, and HDL maturation is impaired in CKD. This study was designed to examine the antioxidant properties of HDL in patients with CKD. In all, 32 stable hemodialysis-dependent patients and 13 age-matched controls were studied. HDL was isolated and used for determination of in vitro antioxidant activity. In addition, the plasma level of key components of HDL, namely paraoxonase (PON), glutathione peroxidase (GPX), platelet activating factor acetylhydrolase (PAF-AH), lecithin cholesterol acyltransferase (LCAT), and apolipoprotein A-I (ApoA-I), were measured. The end-stage renal disease (ESRD) patients exhibited significant reductions of HDL-cholesterol, ApoA-I (-41%), GPX (-50%), and LCAT (-60%) concentrations, and a decrease in PON (-30%) and GPX (-50%) activities. These results were accompanied by a marked reduction of antioxidant activity of HDL (-127%), which was unaffected by the hemodialysis procedure. Thus, in addition to diminished plasma HDL concentration, the composition and antioxidant activity of HDL are altered in CKD; these events can contribute to a heightened risk of atherosclerosis.
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PMID:Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. 1913 52

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.
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PMID:Crystallization and preliminary X-ray crystallographic analysis of human plasma platelet activating factor acetylhydrolase. 1914 81

The vascular inflammatory role of platelet activating factor acetylhydrolase (PAF-AH) is thought to be due to the formation of lysophosphatidyl choline and oxidized non-esterified fatty acids. This enzyme is considered a promising therapeutic target for the prevention of atherosclerosis and there is a need to expand the available chemical templates of PAF-AH inhibitors. This study demonstrated how natural PAF-AH inhibitory peptides were isolated and characterized from the red macroalga Palmaria palmata. The dried powdered alga was hydrolyzed using the food grade enzyme papain, and the resultant peptide containing fraction generated using RP-HPLC. Several oligopeptides were identified as potential PAF-AH inhibitors following bio-guided fractionation, and the amino acid sequences of these oligopeptides were confirmed by Q-TOF-MS and microwave-assisted solid phase de novo synthesis. The most promising PAF-AH inhibitory peptide had the amino acid sequence NIGK and a PAF-AH IC50 value of 2.32 mM. This peptide may constitute a valid drug template for PAF-AH inhibitors. Furthermore the P. palmata hydrolysate was nontoxic when assayed using the Zebrafish toxicity model at a concentration of 1mg/ml.
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PMID:Development of a seaweed derived platelet activating factor acetylhydrolase (PAF-AH) inhibitory hydrolysate, synthesis of inhibitory peptides and assessment of their toxicity using the Zebrafish larvae assay. 2414 Apr 4

High-density lipoprotein (HDL) is composed of apolipoproteins, lipids and functional proteins. HDL protects against atherosclerosis (AS) by reverse cholesterol transport (RCT). HDL inhibits the lipid oxidation, inflammation and restores endothelial function. During systemic inflammation or metabolic disorders, HDL can be modified abnormally and converted to a dysfunctional type, which results in the loss of anti-inflammatory factors including apolipoprotein A-I (apoA-I), paraoxonase (PON) and platelet activating factor acetylhydrolase (PAF-AH), and gains of pro-inflammatory factors such as serum amyloid A (SAA), triglyceride (TG) and oxidative lipid. Therefore, understanding the changes in compositions and biological functions of dysfunctional HDL might help to comprehend its pathogenic mechanism.
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PMID:[Changes in biological functions of high-density lipoprotein after abnormal modification]. 2843 82