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)

Phosphatidylcholines (1-O-alcoxy-2-amino-2-desoxy-phosphocholines and 1-pyrene-labeled analogs) were synthesized and used to examine interactions with recombinant human PAF-acetylhydrolase (PAF-AH), an enzyme purified from plasma, and with macrophage-like U937 cells. Novel phosphatidylcholines containing a sn-2-carbamoylester group such as 1-O-hexadecyl-2-desoxy-2-amino-methylcarbamoyl-2-methyl-rac-glycer o-3-phosphocholine 11 were found to act as site-specific irreversible enzyme inhibitors with Ki-values up to 83 (K(irev)) and 177 (Ki(inact)) microm. The compounds exhibit only marginal inhibition of Ca2+-dependent phospholipases. Kinetic data show that phosphocholines carrying a terminal sn-1-pyrene moiety inhibit PAF-AH activity with an effectivity similar to analogs with an aliphatic chain. 1-O-Decyloxy-[10-(4-pyrenyl)-butoxy]-2-desoxy-2-amino-carbamoyl-me thyl-rac(-glycero-3-phosphocholine 13 could be used for enzyme labeling and to demonstrate an inhibitor-enzyme stoichiometry of 0.7:1. At 8 degrees C, the compound accumulated in the membranes of U937 cells, at 37 degrees C it was internalized into intracellular compartments. Structure activity studies in a mixed micelle assay indicated that the inhibition power of reversible and irreversible inhibitors increases along with the (sn)-1-chain length similar to the structure-dependent binding of ether phospholipids to the PAF-receptor. Unlike the situation at the (sn)-1-position, increasing chain length at the sn-2-position, or an alkyl branching of the glycerol backbone significantly reduced the inhibitory potency.
Atherosclerosis 1999 May
PMID:Novel reversible, irreversible and fluorescent inhibitors of platelet-activating factor acetylhydrolase as mechanistic probes. 1038 Dec 81

The oxidative hypothesis of atherosclerosis classically implies a central role for low density lipoprotein (LDL) oxidation. However, new antiatherogenic properties have been recognized for high density lipoproteins (HDL), apart from their ability to reverse cholesterol transport. Indeed, native HDL could protect LDL from oxidation, thereby minimizing the deleterious consequences of this process. Several mechanisms have been suggested to explain this protective role. Two HDL-associated enzymes, paraoxonase and PAF-acetylhydrolase, detoxify oxidized phospholipids produced by lipid peroxidation. In addition, HDL could reduce hydroperoxides to their corresponding hydroxides. It has also been suggested that HDL could inhibit oxidized LDL-induced transduction signals. However, in vivo HDL oxidation in the subendothelial space would favor the atherosclerotic process. Indeed, atherogenic properties of these oxidized HDL partly result from some loss of their cholesterol effluxing capacity and from an inactivation of the lecithin-cholesterol acyltransferase, which is a HDL-associated enzyme involved in reverse cholesterol transport. Finally, oxidized HDL could induce cholesterol accumulation in macrophages. Further in-depth investigation is needed to assess these antagonistic effects and their consequences for the atherosclerotic process.
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PMID:High density lipoproteins (HDL) and the oxidative hypothesis of atherosclerosis. 1061 47

Platelet activation is involved in serious pathological situations, including atherosclerosis and restenosis. It is important to find efficient antiplatelet medicines to prevent fatal thrombous formation during the course of these diseases. Marchantinquinone, a natural compound isolated from Reboulia hemisphaerica, inhibited platelet aggregation and ATP release stimulated by thrombin (0.1 units mL(-1)), platelet-activating factor (PAF; 2 ng mL(-1)), collagen (10 microg mL(-1)), arachidonic acid (100 microM), or U46619 (1 microM) in rabbit washed platelets. The IC50 values of marchantinquinone on the inhibition of platelet aggregation induced by these five agonists were 62.0 +/- 9.0, 86.0 +/- 7.8, 13.6 +/- 4.7, 20.9 +/- 3.1 and 13.4 +/- 5.3 microM, respectively. Marchantinquinone inhibited thromboxane B2 (TxB2) formation induced by thrombin, PAF or collagen. However, marchantinquinone did not inhibit TxB2 formation induced by arachidonic acid, indicating that marchantinquinone did not affect the activity of cyclooxygenase and thromboxane synthase. Marchantinquinone did inhibit the rising intracellular Ca2+ concentration stimulated by the five platelet-aggregation inducers. The formation of inositol monophosphate induced by thrombin was inhibited by marchantinquinone. Platelet cAMP and cGMP levels were unchanged by marchantinquinone. The results indicate that marchantinquinone exerts antiplatelet effects by inhibiting phosphoinositide turnover.
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PMID:Antiplatelet effect of marchantinquinone, isolated from Reboulia hemisphaerica, in rabbit washed platelets. 1075 26

Platelet-activating factor acetylhydrolase (PAF-AH), a plasma enzyme that hydrolyzes PAF and oxidized phospholipids, is thought to be involved in protecting cells against oxidative stress. A G(994) (M allele)-->T (m allele) mutation in the plasma PAF-AH gene, which results in a Val(279)-->Phe substitution in the mature protein, leads to a loss of catalytic activity. To elucidate the relationships among PAF-AH enzyme activity, genotype, age, and atherosclerosis, we assayed these parameters in a large Japanese population (n=3932) that consisted of three groups; a control group (healthy individuals; n=1684), a risk-factor group (individuals having at least one conventional risk factor for atherosclerosis; n=1398), and a diseased group (patients who had suffered a myocardial infarction or stroke; n=850). We observed a significantly increased frequency of the m allele in the diseased group as compared with the control or risk-factor groups. Plasma PAF-AH activity increased significantly with age in women in the control group with the MM and Mm genotypes, and in men in the control group with the MM genotype, but not in men with the Mm genotype. In both the risk-factor and diseased groups, however, no correlation was observed between plasma PAF-AH activity and age in subjects with either genotype. These results suggest that in individuals with the MM genotype, plasma PAF-AH activity may be increased in response to stresses induced by PAF and/or oxidized phospholipids that might accumulate with age, but that this response is not evident or reduced in healthy individuals with the m allele, or in subjects with atherosclerotic disease, or having risk factors. Together with our previous findings, the G(994)-->T mutation in the PAF-AH gene may be one of the genetic determinants for atherosclerotic disease in the Japanese population.
Atherosclerosis 2000 May
PMID:Correlations between plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and PAF-AH genotype, age, and atherosclerosis in a Japanese population. 1078 53

Macrophage infiltration into the subendothelial space at lesion prone sites is the primary event in atherogenesis. Inhibition of macrophage homing might therefore prevent atherosclerosis. Since HDL levels are inversely correlated with cardiovascular risk, their effect on macrophage homing was assessed in apoE-deficient (apoE-/-) mice. Overexpression of human apolipoprotein AI in apoE-/- mice increased HDL levels 3-fold and reduced macrophage accumulation in an established assay of leukocyte homing to aortic root endothelium 3.2-fold (P<0.005). This was due to reduced in vivo betaVLDL oxidation, reduced betaVLDL triggered endothelial cytosolic Ca2+ signaling through PAF-like bioactivity, lower ICAM-1 and VCAM-1 expression, and diminished ex vivo leukocyte adhesion. Adenoviral gene transfer of human PAF-acetylhydrolase (PAF-AH) in apoE-/- mice increased PAF-AH activity 1.5-fold (P<0.001), reduced betaVLDL-induced ex vivo macrophage adhesion 3.5-fold (P<0.01), and reduced in vivo macrophage homing 2.6-fold (P<0.02). These inhibitory effects were observed in the absence of increased HDL cholesterol levels. In conclusion, HDL reduces macrophage homing to endothelium by reducing oxidative stress via its associated PAF-AH activity. This protective mechanism is independent of the function of HDL as cholesterol acceptor. Modulation of lipoprotein oxidation by PAF-AH may prevent leukocyte recruitment to the vessel wall, a key feature in atherogenesis.
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PMID:HDL-associated PAF-AH reduces endothelial adhesiveness in apoE-/- mice. 1102 87

In order to identify potential atherogenic properties of gas-phase cigarette smoke, we utilized an in vitro exposure model to determine whether the activities of several putative anti-atherogenic enzymes associated with plasma lipoproteins were compromised. Exposure of heparinized human plasma to gas-phase cigarette smoke produced a dose-dependent reduction in the activity of platelet-activating factor acetylhydrolase (PAF-AH). Reductions of nearly 50% in PAF-AH activity were observed following exposure to gas-phase smoke from four cigarettes over an 8-h period. During this time of exposure, lecithin:cholesterol acyltransferase (LCAT) was rendered almost completely inactive (>80%). In contrast, paraoxonase was totally unaffected by cigarette smoke. Supplementation of plasma with 1 mM reduced glutathione was found to protect both PAF-AH and LCAT from cigarette smoke, suggesting that cysteine modifications may have contributed to the inhibition of these two enzymes. To evaluate this possibility, we blocked the free cysteine residues of these enzymes with the reversible thiol-modifying reagent dithiobisnitrobenzoic acid (DTNB). Reversal of the DTNB-cysteine adducts following cigarette smoke exposures revealed that LCAT, but not PAF-AH, was protected. Moreover, high doses (1.0-10 mM) of acrolein and 4-hydroxynonenal, reactive aldehydic species associated with cigarette smoke, completely inhibited plasma LCAT activity, whereas PAF-AH was resistant to such exposures. Taken together, these results indicate a divergence regarding the underlying mechanism of PAF-AH and LCAT inhibition upon exposure to gas-phase cigarette smoke. While LCAT was sensitive to exposure to volatile aldehydic products involving, in part, cysteine and/or active site modifications, the enzyme PAF-AH exhibited an apparent resistance. The latter suggests that the active site of PAF-AH is in a microenvironment that lacks free cysteine residues and/or is shielded from volatile aldehydic combustion products. Based on these results, we propose that cigarette smoke may contribute to atherogenesis by inhibiting the activities of plasma PAF-AH and LCAT, but the nature of this inhibition differs for the enzymes.
Atherosclerosis 2001 Mar
PMID:Relative sensitivities of plasma lecithin:cholesterol acyltransferase, platelet-activating factor acetylhydrolase, and paraoxonase to in vitro gas-phase cigarette smoke exposure. 1122 28

Increased LDL oxidation is associated with coronary artery disease. The predictive value of circulating oxidized LDL is additive to the Global Risk Assessment Score for cardiovascular risk prediction based on age, gender, total and HDL cholesterol, diabetes, hypertension, and smoking. Circulating oxidized LDL does not originate from extensive metal ion-induced oxidation in the blood but from mild oxidation in the arterial wall by cell-associated lipoxygenase and/or myeloperoxidase. Oxidized LDL induces atherosclerosis by stimulating monocyte infiltration and smooth muscle cell migration and proliferation. It contributes to atherothrombosis by inducing endothelial cell apoptosis, and thus plaque erosion, by impairing the anticoagulant balance in endothelium, stimulating tissue factor production by smooth muscle cells, and inducing apoptosis in macrophages. HDL cholesterol levels are inversely related to risk of coronary artery disease. HDL prevents atherosclerosis by reverting the stimulatory effect of oxidized LDL on monocyte infiltration. The HDL-associated enzyme paraoxonase inhibits the oxidation of LDL. PAF-acetyl hydrolase, which circulates in association with HDL and is produced in the arterial wall by macrophages, degrades bioactive oxidized phospholipids. Both enzymes actively protect hypercholesterolemic mice against atherosclerosis. Oxidized LDL inhibits these enzymes. Thus, oxidized LDL and HDL are indeed antagonists in the development of cardiovascular disease.
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PMID:Oxidized LDL and HDL: antagonists in atherothrombosis. 1164 Dec 34

We examined whether the putative anti-atherogenic enzymes LCAT, paraoxonase (PON), and platelet-activating factor acetylhydrolase (PAF-AH) are impaired in 8 week old atherosclerosis susceptible apolipoprotein E (apoE)(-/-) and LDL receptor (LDLr)(-/-) mice and whether plasma concentrations of bioactive oxidized phospholipids accumulate in plasma. ApoE(-/-) mice had reduced (28%) LCAT activity and elevated lysophosphatidylcholine and bioactive oxidized phospholipids (1-palmitoyl-2-oxovaleryl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine) compared with controls on the chow diet. Elevated oxidized phospholipids and reduced LCAT activity may, in part, contribute to spontaneous lesions in these mice on a chow diet. A Western diet decreased LCAT activity further (50% of controls) and PON activity was decreased 38%. The LDLr(-/-) mice showed normal LCAT activity on chow diet and little accumulation of oxidized phospholipids. On a Western diet, LDLr(-/-) mice had reduced LCAT activity (21%), but no change in PON activity. All genotypes had reduced PAF-AH activity on the Western diet. ApoE(-/-) and LDLr(-/-) mice, but not controls, had elevated plasma bioactive oxidized phospholipids on the Western diet. We conclude that impairment of LCAT activity and accumulation of oxidized phospholipids are part of an early atherogenic phenotype in these models.
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PMID:Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet-activating factor acetylhydrolase in atherosclerosis-susceptible mice. 1189 84

Diabetes mellitus (DM) is accompanied by several cardiovascular complications such as coronary artery disease, atherosclerosis, hypertension, cerebral and myocardial infarction, etc. DM induces the alteration of platelet functions including activation, hyperaggregation, adhesiveness, and formation of thrombi. Release of AA from phospholipids of the PM, synthesis of TxA(2),PGE(2), activity of PLA(2), and PLC are increased in the platelets of the DM patients. Stimulation of PLA(2) activity and accumulation of bioactive metabolites such as AA, its oxygenated derivatives, prostaglandins and PAF can evoke glucose production, also. In this study we explored the effect of the 1,4-dihydropyridine compound cerebrocrast at a low concentration (10(-6)-10(-8)M) on the level of intracellular calcium in unstimulated human platelets and those stimulated with thrombin as well as release of [(3)H] AA from phospholipids of platelet PM. Cerebrocrast at a concentration of 10(-6) M decreased the basal level of intracellular calcium concentration (platelets were loaded with Fura-2) in unstimulated as well as in thrombin stimulated platelets. Cerebrocrast at concentrations of 10(-6), 10(-7), 10(-8) M inhibited release of [(3)H] AA from phospholipids of platelet PM. We conclude that blockade of human platelet activation with cerebrocrast can prevent aggregation, adhesion and formation of thrombi. The inhibition of [(3)H] AA release from phospholipids of platelet PM can prevent formation of eicosanoids such as TxA(2), PGG(2), and PGH(2) plus AA oxygenated derivatives. These effects of cerebrocrast are very significant in the treatment of DM-evoked cardiovascular complications.
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PMID:Effect of cerebrocrast on the function of human platelets and release of the arachidonic acid from plasma membrane. 1197 14

Inflammation underlies both onset and perpetuation of atherosclerosis. Plasma lipoproteins transport the platelet-activating factor-acetylhydrolase (PAF-AH) with potentially anti-inflammatory activities. Our aim was to determine whether PAF-AH activity was associated with inflammatory markers and with coronary artery disease (CAD). PAF-AH activity and a panel of inflammatory mediators were measured in plasma of 496 patients with CAD and in 477 controls; 276 patients presented with stable angina pectoris and 220 with acute coronary syndrome (ACS). Individuals within the highest quartile of PAF-AH activity had an 1.8-fold increase in CAD risk [95% confidence interval (CI), 1.01 to 3.2; P = 0.048] compared with those in the first quartile (adjusted for clinical and metabolic factors). When excluding individuals receiving statin and angiotensin-converting enzyme-inhibitor medication, individuals within the highest quartile of PAF-AH activity revealed a 3.9-fold increase in CAD risk (95% CI, 2.0 to 7.7; P < 0.0001). In these subjects, the plasma PAF-AH activity increased gradually in stable angina and in ACS both in men (P < 0.0001) and in women (P < 0.001), as compared with controls. No correlation was found between PAF-AH levels and those of common markers of inflammation. This study and the previous ones raise the important issue of whether PAF-AH is simply a marker of risk or directly promotes atherosclerosis.
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PMID:Plasma PAF-acetylhydrolase in patients with coronary artery disease: results of a cross-sectional analysis. 1273 Feb 97


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