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)

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men, 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Val279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia.
Atherosclerosis 2004 Jan
PMID:Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. 1470 72

Animal models provide vital tools to explicate the pathogenesis of atherosclerosis. Accordingly, we established two atherosclerosis-prone mice models: (i) mice lacking the LDL (low-density lipoprotein) receptor (LDLR) and the ability to edit apo (apolipoprotein) B mRNA (Apobec1; designated LDb : LDLR-/- Apobec1-/-), and (ii) mice with the LDb background, who also overexpressed human apoB100 (designated LTp : LDLR-/- Apobec1-/- ERhB+/+). Both LDb and LTp mice had markedly elevated levels of LDL and increased levels of NEFAs (non-esterified fatty acids) compared with C57BL/6 wild-type mice. However, fasting glucose and insulin levels in both animals were not different than those in C57BL/6 wild-type mice. It has been suggested that PAF-AH (platelet-activating factor acetylhydrolase) increases susceptibility to vascular disease. Both LDb and LTp mice had significantly higher PAF-AH mRNA levels compared with C57BL/6 wild-type mice. PAF-AH gene expression was also significantly influenced by age and sex. Interestingly, PAF-AH mRNA levels were significantly higher in both LTp male and female mice than in the LDb mice. This increased PAF-AH gene expression was associated with elevated plasma PAF-AH enzyme activities ( LTp > LDb > C57BL/6 ). Moreover, a greater proportion of PAF-AH activity was associated with the apoB-containing lipoproteins: 29% in LTp and 13% in LDb mice compared with C57BL/6 wild-type animals (6.7%). This may explain why LTp mice developed more atherosclerotic lesions than LDb mice by 8 months of age. In summary, increased plasma NEFAs, PAF-AH mRNA and enzyme activities are associated with accelerated atherogenesis in these animal models.
 ...
PMID:Increased plasma non-esterified fatty acids and platelet-activating factor acetylhydrolase are associated with susceptibility to atherosclerosis in mice. 1471 54

Type VII phospholipase A2 associated to low density lipoproteins (LDL), also known as platelet-activating factor acetylhydrolase, has been recently indicated as a new non traditional and independent risk factor of coronary disease. After the classification of phospholipase A2 family enzymes, a review is made of the recent physiologic and biochemical knowledges on A2 type VII phospholipase LDL lipoproteins-associated and the role developed in lipoproteins metabolism and atherogenesis. Finally, future therapeutic implications and perspectives depending on these knowledges are pointed out especially by using molecules inhibiting the activity of the enzyme in atherosclerosis therapy. The evaluation of circulating activity of the enzyme may be useful in the prevention and recognition of acute coronary syndromes.
 ...
PMID:[Lipoprotein-associated phospholipase A2: importance and perspectives]. 1527 48

We have previously shown that intravenous apolipoprotein (apo) A-I/phosphatidylcholine (apo A-I/PC) discs increase plasma high-density lipoprotein (HDL) concentration in humans. We have now studied the associated changes in two enzymes, paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH) that are carried in whole or in part by HDLs, and are thought to influence atherogenesis by hydrolyzing oxidized phospholipids in lipoproteins. Apo A-I/PC discs (40 mg/kg over 4 h) were infused into eight healthy males. Although plasma apo A-I and HDL cholesterol increased on average by 178 and 158%, respectively, plasma total PON and total PAF-AH concentrations did not rise. By the end of the infusion, HDL-associated PAF-AH had increased by 0.56 +/- 0.14 microg/mL (mean +/- S.D., P < 0.01), and nonHDL-associated PAF-AH had decreased by 0.84 +/- 0.11 microg/mL (P < 0.05). These changes were accompanied by an increase in the HDL-associated PAF-AH/apo A-I ratio from 0.19 to 0.35 (P < 0.05), and by a decrease in the nonHDL-associated PAF-AH/apo B ratio from 2.1 to 1.4 (P < 0.05). No changes in PON or PAF-AH concentrations were detected in prenodal lymph (tissue fluid), collected continuously from the leg. Our results show that the total concentrations of PON and PAF-AH in plasma are uninfluenced by plasma HDL concentration. PAF-AH transfers readily between HDLs and LDLs in vivo, and its distribution between them is determined partly by their relative concentrations and partly by HDL composition.
Atherosclerosis 2004 Sep
PMID:Effects of intravenous apolipoprotein A-I/phosphatidylcholine discs on paraoxonase and platelet-activating factor acetylhydrolase in human plasma and tissue fluid. 1530 75

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.
 ...
PMID:Thematic review series: The immune system and atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? 1572 58

Carotid intima media thickness (IMT), represents an important clinical indicator of early atherosclerosis. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme primarily associated with low-density lipoprotein (LDL) while a small proportion of enzymatic activity is also associated with high-density lipoprotein (HDL). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. The authors investigated the possible relationship between carotid IMT and the plasma levels of PAF-AH mass and activity as well as the PON1 activity in hyperlipidemic patients. One hundred unrelated patients with primary hyperlipidemia and 67 age-and sex-matched normolipidemic apparently healthy volunteers participated in the study. The PAF-AH activity in total plasma and in HDL-rich plasma (HDL-PAF-AH activity), the plasma PAF-AH mass, and the serum PON1 activities toward paraoxon and phenyl acetate were determined. The plasma PAF-AH mass and activity were higher in hyperlipidemic patients compared to controls, whereas the HDL-PAF-AH activity, as well as the serum PON1 activities were not significantly different between the studied groups. When hyperlipidemic patients were divided into 2 subgroups according to their IMT values (IMT <0.7 mm and IMT > or =0.7 mm) patients with IMT > or =0.7 mm had significantly higher age, and serum triglyceride concentrations, whereas no difference was found in the plasma PAF-AH mass and activity as well as in the HDL-PAF-AH activity between the 2 studied subgroups. The same phenomenon was observed for serum PON1 activities. In a multivariate analysis, only the age was significantly correlated with IMT values (p<0.05). Neither the total plasma PAF-AH mass and activity nor the HDL-PAF-AH activity are associated with early carotid atherosclerosis.
 ...
PMID:Lack of association between carotid intima-media thickness and PAF-acetylhydrolase mass and activity in patients with primary hyperlipidemia. 1607 29

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), also known as platelet-activating factor acetylhydrolase, is a plasma enzyme that circulates bound to lipoproteins. The association between Lp-PLA(2) and atherosclerosis is ambiguous, as it can both degrade and generate potentially damaging vasoactive molecules. In this article, we speculate that Lp-PLA(2) associated with HDL might have cardioprotective properties, whereas the same enzyme bound to LDL might contribute directly to atherosclerosis at all stages, from lipoprotein oxidation to endothelial dysfunction, and plaque initiation and growth. Genetic and animal model studies give varying indications as to the contribution of Lp-PLA(2) to atherogenesis and tend to support the view that higher Lp-PLA(2) levels are cardioprotective. By contrast, a series of population studies point clearly to a positive association between plasma Lp-PLA(2) levels or activity levels and risk of coronary heart disease or stroke. Typically, people with Lp-PLA(2) levels in the highest quintile of the population have about a twofold greater risk than those in the lowest quintile. It is, perhaps, too early to introduce Lp-PLA(2) as a population-wide biomarker for coronary heart disease risk; however, with accumulating evidence, it might find a place in a stepwise risk assessment of individuals who require more aggressive intervention to prevent vascular disease.
 ...
PMID:Lipoprotein-associated phospholipase A2 as a biomarker for coronary disease and stroke. 1618 51

Lipoprotein associated phospholipase A2 (Lp-PLA2) modulates low-density lipoprotein (LDL) oxidation by hydrolysing oxidised phospholipids present on particle surfaces. We investigated whether Lp-PLA2 activity and PLA2G7 A379V genotype were related to mediators of atherosclerosis in a diabetic study. Plasma Lp-PLA2 activity (taken in men only) and A379V genotype were investigated with regards to metabolic syndrome (MS), UKPDS risk score, and oxidised LDL (oxLDL/LDL), in a cohort of Caucasian men and women (n=783, age 62.5+/-13.7 years). After adjustment for type of diabetes, CHD status, and statin use, those individuals with features defining the MS (WHO guidelines) had higher Lp-PLA2 activity (35.6+/-11.9 nmol/min/ml) compared to those without (33.0+/-10.8 nmol/min/ml) (p=0.02). Quartiles of UKPDS coronary heart disease (CHD) risk score were also positively associated with Lp-PLA2 activity (p=0.006, p=0.004 linear trend). Those men in the highest quartile of oxLDL/LDL level had the lowest Lp-PLA2 activity (31.3+/-10.5 nmol/min/ml) when compared to the middle two (32.3+/-9.8 and 35.9+/-10.9 nmol/min/ml, respectively) and lowest quartile (35.6 +/-12.5 nmol/min/ml; p=0.03, p=0.004 linear trend). There was no significant association between A379V genotype and Lp-PLA2 enzyme activity (p=0.34) or oxLDL/LDL (p=0.32). Lp-PLA2 activity is an independent predictor of CHD risk and MS in a sample of subjects with diabetes mellitus. The association of Lp-PLA2 activity with oxLDL/LDL suggests that Lp-PLA2 may be a modulating factor in the process of atherosclerosis.
Atherosclerosis 2006 Nov
PMID:Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus. 1643 75

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

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


<< Previous 1 2 3 4 Next >>