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)

15-lipoxygenase is a lipid-peroxidating enzyme that oxidizes fatty acids, such as those esterified to cellular membranes. It has been implicated in the oxidative modification of low-density lipoprotein and is thus thought to contribute to the development of atherosclerosis. The enzyme has also been shown to be specifically induced by interleukin-4 in human blood monocytes. Two 15-lipoxygenase-hybridizing messages were detected in these cells; one (2.7 kb) corresponds to the previously isolated cDNA for 15-lipoxygenase, while the other (4 kb) was of unknown origin. We have isolated and characterized this 4 kb transcript. Our experiments show that it has 1.2 kb additional sequence in its 3' untranslated region, and that it is generated from genomic sequences through differential polyA site selection. We present studies to address the functional significance of the extended 3'UTR. Selection of an upstream polyadenylation signal results in production of the 2.7 kb transcript. In addition, we present here for the first time the cloning and sequence of the human 15-lipoxygenase gene, as well as the identification of regulatory elements in the promoter region of this gene.
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PMID:Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene. 922 51

Neuronal nitric oxide synthase (nNOS) has been implicated in a wide variety of physiological and pathological processes. These include neurotransmission, neurotoxicity, skeletal muscle contraction, sexual function, body fluid homeostasis and atherosclerosis, among others. Consistent with the involvement of nNOS in such varied aspects of cellular biology, nNOS mRNA and protein are expressed in numerous tissues. Both its gene structure and expressional regulation are exceedingly complex. Characterization of the genomic organization of the human nNOS has revealed that the transcription unit of 29 exons spans a region greater than 240 kb at 12q24.2. The gene produces multiple mRNA transcripts via a variety of intriguing mechanisms: alternate promoter usage, alternative splicing, cassette insertions/deletions, and varied sites for 3'-UTR cleavage and polyadenylation. Allelic diversity in mRNA structure also exists. Some, but not all, of these various transcripts affect the encoded amino acid sequence and translate into nNOS protein isoforms with altered structural and functional properties. Interestingly, much of this diversity is restricted to the untranslated regions of the mRNA transcript and may affect its translation or stability. Taken together, these properties present nNOS as one of the most complex human genes described to date. Given the importance of nNOS in human health and disease, understanding this intricate genetic regulation has been a major focus in nNOS research. This review addresses the structure of the nNOS gene, its mRNA diversity, and overall genetic regulation with an emphasis on their biological implications.
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PMID:Neuronal NOS: gene structure, mRNA diversity, and functional relevance. 1022 22

Cardiovascular disease is accompanied by an impaired endothelium-dependent vasodilatory response. Loss of endothelial nitric oxide synthase (eNOS) expression may contribute to endothelial dysfunction. The aim of the present study was to analyze the effect of cerivastatin, a novel HMG CoA reductase inhibitor, on tumor necrosis factor-alpha (TNF-alpha)-induced downregulation of eNOS protein expression in bovine aortic endothelial cells (BAEC). TNF-alpha (10 ng/ml)- incubated BAEC showed a reduced expression of eNOS protein and decreased eNOS mRNA stabilization. This effect was associated with an increased binding activity of BAEC cytosolic proteins to the 3'-untranslated region (3'UTR) of eNOS mRNA. Cerivastatin prevented TNF-alpha-induced downregulation of eNOS protein expression in a concentration-dependent manner (10(-8) to 10(-5) M). Cerivastatin also prevented the binding of the cytosolic proteins to 3'-UTR of eNOS mRNA and was associated with eNOS mRNA stabilization. The reduced expression of eNOS protein by TNF-alpha was also prevented by coincubation with cycloheximide. In addition cycloheximide inhibited the binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA, suggesting the inducible character of the mentioned-cytosolic proteins. TNF-alpha stimulated the translocation of nuclear factor-kappaB (NF-kappaB), an effect that was not modified by cerivastatin. Furthermore, an inhibitor of NF-kappaB translocation, pyrrolidine dithiocarbamate failed to modify both the downregulation of eNOS expression and the increased binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA by TNF-alpha. The effect of cerivastatin on eNOS expression and the binding activity of the cytosolic proteins were reversed by coincubation with L-mevalonate. In conclusion, cerivastatin stabilized eNOS mRNA and upregulated eNOS expression in the endothelium, and this was associated with a decreased binding activity of cytosolic proteins to 3'-UTR of eNOS mRNA. The effect of cerivastatin on the regulation of eNOS expression was independent of NF-kappaB mobilization by TNF-alpha. These findings suggest that cerivastatin may have beneficial effects on the endothelial dysfunction associated with cardiovascular diseases beyond its effect on lowering cholesterol.
Atherosclerosis 2001 Mar
PMID:Cerivastatin prevents tumor necrosis factor-alpha-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins. 1122 27

Human HDL-associated paraoxonase (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces oxidation of LDLs and HDLs. These properties of PON1 account for its ability to protect against pesticide poisonings and atherosclerosis. PON1 also hydrolyzes a number of lactone and cyclic-carbonate drugs. Among individuals in a population, PON1 levels vary widely. We previously identified three polymorphisms in the PON1 regulatory region that affect expression levels in cultured human hepatocytes. In this study, we determined the genotypes of three regulatory-region polymorphisms for 376 white individuals and examined their effect on plasma-PON1 levels, determined by rates of phenylacetate hydrolysis. The -108 polymorphism had a significant effect on PON1-activity level, whereas the -162 polymorphism had a lesser effect. The -909 polymorphism, which is in linkage disequilibrium with the other sites, appears to have little or no independent effect on PON1-activity level in vivo. Other studies have found that the L55M polymorphism in the PON1-coding region is associated with differences in both PON1-mRNA and PON1-activity levels. The results presented here indicate that the L55M effect of lowered activity is not due to the amino acid change but is, rather, largely due to linkage disequilibrium with the -108 regulatory-region polymorphism. The codon 55 polymorphism marginally appeared to account for 15.3% of the variance in PON1 activity, but this dropped to 5% after adjustments for the effects of the -108 and Q192R polymorphisms were made. The -108C/T polymorphism accounted for 22.8% of the observed variability in PON1-expression levels, which was much greater than that attributable to the other PON1 polymorphisms. We also identified four sequence differences in the 3' UTR of the PON1 mRNA.
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PMID:Effects of 5' regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. 1133 91

The low-density lipoprotein receptor (LDLR) has been proposed to promote hepatitis C virus endocytosis and the cell membrane protein CD81 may also promote HCV host cell entry. The CD81 gene was sequenced to screen for novel polymorphisms, but no SNPs were identified. Polymorphisms within the LDLR gene are associated with the pathogenesis of familial hypercholesterolemia, atherosclerosis and obesity. We therefore studied genetic variation within the LDLR gene and clinical features of hepatitis C infection. An amino acid change in exon 8 was associated with severity of fibrosis; a SNP in exon 10 correlated with viral clearance and overall inflammation, and a SNP in the 3'UTR appeared to influence treatment response. There were no other significant associations between any of the SNPs studied and the clinical measures of hepatitis C infection. We furthermore report on linkage disequilibrium within the gene and haplotype frequencies in our population. Our findings support a possible role for the LDLR in the modulation of disease progression by affecting immune responses, rather than functioning as receptor for HCV.
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PMID:Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection. 1220 63

Gene expression profiling was carried out comparing Con A elicited peritoneal macrophages from C57BL6 and FVBN wild-type and apolipoprotein (apo)E knockout mice. An EST, was expressed at higher levels in C57BL6 compared with FVBN mice. mapped to an atherosclerosis susceptibility locus on chromosome 19 revealed in an intercross between atherosclerosis-susceptible C57BL6 and atherosclerosis-resistant FVBN apoE knockout mice. A combination of database search and Northern analysis confirmed that corresponded to 3'-UTR of a hitherto predicted gene, named HspA12A. Blasting the National Center for Biotechnology Information database revealed a closely related homologue, HspA12B. HspA12A and -B have very close human homologues. TaqMan analysis confirmed the increased HspA12A expression (2.6-fold) in elicited peritoneal macrophages from C57BL6 compared with FVBN mice. TaqMan analysis also revealed increased HspA12A and HspA12B expression (87- and 6-fold, respectively) in lesional versus nonlesional portions of the thoracic aorta from C57BL6 apoE knockout mice on a chow diet. In situ hybridization confirmed that both genes were expressed within lesions but not within nonlesional aortic tissue. Blasting of HspA12A and HspA12B against the National Center for Biotechnology Information database (NR) revealed a hit with the Conserved Domain database for Hsp70 (pfam00012.5, Hsp70). Both genes appear to contain an atypical Hsp70 ATPase domain. The BLAST search also revealed that both genes were more similar to primitive eukaryote and prokaryote than mammalian Hsp70s, making these two genes distant members of the mammalian Hsp70 family. In summary, we describe two genes that code for a subfamily of Hsp70 proteins that may be involved in atherosclerosis susceptibility.
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PMID:Two Hsp70 family members expressed in atherosclerotic lesions. 1255 99

A 53G>A polymorphism identified in the 5' untranslated region (5'UTR) of the platelet endothelial cell adhesion molecule-1 (PECAM-1) gene alters a putative shear stress responsive element (SSRE). PECAM-1 was shown to be responsive to shear stress and transient transfection of human umbilical vein endothelial cell (HUVECs) with two luciferase reporter constructs driven by the PECAM-1 promoter and 5'UTR showed a response of the 53G allele, not the 53A allele, to shear stress. Association between the 53G>A, and the previously published L125V polymorphism, and coronary atherosclerosis was examined in two angiographic studies. The frequencies of the rare alleles of the 53G>A and L125V polymorphisms were 0.01 and 0.49, respectively, in the Lopid Coronary Angiography Trial (LOCAT) study and 0.02 and 0.49, respectively, in the Regression Growth Evaluation Statin Study (REGRESS) study. Compared with 53G homozygotes, carriers of the 53A allele showed less focal progression of disease in the LOCAT study and a similar trend in the diffuse progression of disease in the REGRESS study, whereas no association between L125V and coronary atherosclerosis was observed in either study. These data demonstrate that the PECAM-1 gene is responsive to shear stress in vitro and that decreased PECAM-1 gene expression in 53A carriers may influence reduced progression of vessel stenosis in patients with coronary artery disease.
Atherosclerosis 2003 May
PMID:A novel functional polymorphism in the PECAM-1 gene (53G>A) is associated with progression of atherosclerosis in the LOCAT and REGRESS studies. 1273 96

To better understand the role of cholesteryl ester transfer protein (CETP) in cardiovascular disease, nine polymorphisms spanning the gene from the upstream promoter region to beyond the 3'UTR were genotyped in 2553 individuals from multiple ethnic groups and with different cardiovascular disease profiles. The frequency of four of these SNPs varied by 40-300% between Caucasians and African Americans. SNPs in each ethnic group fell into two haploblocks with significant linkage disequilibrium within each block. SNPs in the 5' haploblock were significantly associated with HDL cholesterol while SNPs in the 3' haploblock were, at best, only weakly associated with HDL-C. One SNP in the 3' haploblock (rs1800774 in intron 12) was highly associated with history of myocardial infarction even though it was not associated with HDL-C. This association was driven by the effect in Caucasian women where 11.9% of the women with no history of MI are homozygous for the less common allele while 23.7% of those with a history of MI share this genotype. In addition, this SNP was highly associated with BMI among Caucasians (p < 0.0001). The association of HDL-C with CETP genotype was found to be independent of smoking or alcohol consumption. These results replicate some earlier findings and also help to explain some of the apparent contradictions in the literature surrounding the role of CETP in modulating HDL-C and cardiovascular disease.
Atherosclerosis 2005 Jul
PMID:CETP polymorphisms associated with HDL cholesterol may differ from those associated with cardiovascular disease. 1593 53

The human oxidised low-density lipoprotein receptor 1 (OLR1) gene is a functional candidate for atherosclerosis. An association of the OLR1 gene with acute myocardial infarction (AMI) or coronary artery disease (CAD) has recently been reported. In the present study a total of 677 Italian subjects, 327 CAD-free, 350 CAD, of which 190 with AMI and 160 AMI-free, was genotyped for the following four OLR1 single nucleotide polymorphisms: exon 4 K167N, IVS4 -73C>T, IVS4 -14A>G, and 3'UTR 188 C>T. No statistically significant difference was observed in allele or genotype distribution of the exon 4, intron 4, or 3'UTR SNPs in CAD patients compared to CAD-free subjects, or within CAD, in AMI patients compared to AMI-free patients. A correlation was found between the K167N G/G genotype and the increased number of obstructed vessels. Even if the OLR1 genotype frequency distribution data in CAD or AMI subjects here reported do not fully confirm the positive results of some other association studies, an association with a marker of CAD severity was observed.
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PMID:On the association of the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction or coronary artery disease. 1672 9

Oxidized-low density lipoproteins (ox-LDL) and the specific receptor LOX-1 are involved in atherogenesis and atherothrombosis. LOX-1 downregulation is associated with the anti-platelet action of atorvastatin. 3'UTR/T LOX-1 polymorphism has been associated with increased risk of coronary artery disease. This study was planned to determine whether LOX-1 genetic variations could affect anti-platelet action of atorvastatin. We studied by platelet P-selectin (P-sel), CD36 and LOX-1 expression (cytofluorimetric detection) whether differences in cellular activation could be suitable in 109 3'UTR/T carriers out of 201 hypercholesterolemic subjects treated with atorvastatin 20mg/day. Hyperactivated platelets (P-sel in resting cells and % variation upon thrombin activation, p<0.001) were detected at baseline in patients without significant differences between T or C carriers. P-sel and platelet-associated ox-LDL, were significantly decreased (all p<0.001) in C carriers after one week of treatment before LDL reduction. In 3'UTR/T carriers P-sel was reduced (p<0.01) after 6 weeks of treatment according to LDL and ox-LDL reduction. In 3'UTR/T carriers atorvastatin reduced platelet activity by LDL and ox-LDL lowering and not by rapid CD36 and LOX-1 downregulation as in C carriers. Such data suggest that in T carriers LDL lowering is needed to achieve anti-platelet action.
Atherosclerosis 2005 Dec
PMID:3'UTR/T polymorphism of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with modified anti-platelet activity of atorvastatin in hypercholesterolemic subjects. 1628 95


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