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)

The macrophage is critical to the innate immune response and contributes to human diseases, including inflammatory arthritis and plaque formation in atherosclerosis. Vascular endothelial growth factor (VEGF) is an angiogenic cytokine that is produced by macrophages. To study the regulation of VEGF production in macrophages we show that stimulation of monocyte-macrophage-like RAW-264.7 cells by lipopolysaccharide (LPS) increases expression of VEGF mRNA and protein. Three alternative splicing VEGF mRNA isoforms are produced, and the stability of VEGF mRNA increases following cellular activation. To study post-transcriptional regulation of the VEGF gene the 3'-untranslated region (3' UTR) was introduced into the 3' UTR of the luciferase gene in a reporter construct. In both RAW-264.7 cells and thioglycollate-elicited macrophages, the 3' UTR sequence dramatically reduces reporter expression. Treatment with activators of macrophages, including LPS, lipoteichoic acid, and VEGF protein, stimulates expression of 3' UTR reporters. Finally, mapping studies of the 3' UTR of VEGF mRNA show that deletion of the heterogeneous nuclear ribonucleoprotein l binding site affects basal reporter expression in RAW-264.7 cells, but does not affect reporter activation with LPS. Together these results demonstrate that a post-transcriptional mechanism contributes to VEGF gene expression in activated macrophage cells.
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PMID:VEGF gene expression is regulated post-transcriptionally in macrophages. 1644 60

Tight regulation of COX-2 expression is a key feature controlling eicosanoid production in atherosclerosis and other inflammatory syndromes. Adhesive interactions between platelets and monocytes occur in these conditions and deliver specific signals that trigger inflammatory gene expression. Using a cellular model of monocyte signaling induced by activated human platelets, we identified the central posttranscriptional mechanisms that regulate timing and magnitude of COX-2 expression. Tethering of monocytes to platelets and to purified P-selectin, a key adhesion molecule displayed by activated platelets, induces NF-kappaB activation and COX-2 promoter activity. Nevertheless, COX-2 mRNA is rapidly degraded, leading to aborted protein synthesis. Time-dependent signaling of monocytes induces a second phase of transcript accumulation accompanied by COX-2 enzyme synthesis and eicosanoid production. Here, generation of IL-1beta, a proinflammatory cytokine, promoted stabilization of COX-2 mRNA by silencing of the AU-rich mRNA decay element (ARE) in the 3'-untranslated region (3'UTR) of the mRNA. Consistent with observed mRNA stabilization, activated platelets or IL-1beta treatment induced cytoplasmic accumulation and enhanced ARE binding of the mRNA stability factor HuR in monocytes. These findings demonstrate that activated platelets induce COX-2 synthesis in monocytes by combinatorial signaling to transcriptional and posttranscriptional checkpoints. These checkpoints may be altered in disease and therefore useful as targets for antiinflammatory intervention.
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PMID:Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling. 1699 85

The low-density lipoprotein receptor (LDLR) plays a pivotal role in cholesterol homeostasis. However, the role of genetic variations in the 3'UTR of the LDLR in relation to plasma cholesterol has been largely understudied. Six SNPs, G44243A, G44332A, C44506G, G44695A, C44857T and A44964G, within the 5' region of the 3'UTR fall into three common haplotypes, GGCGCA, AGCACG, and GGCGTA, occurring at frequencies of 0.45, 0.31 and 0.17, respectively, in Caucasians (n = 29) and 0.13, 0.13 and 0.38, respectively, in African Americans (n = 32), with three other haplotypes occurring at lesser frequencies. In a tissue culture based system, expression of a reporter gene carrying a 3'UTR that includes the 1 kb nucleotide sequences corresponding to the AGCACG or GGCGTA was 70 or 63%, respectively, of the same sequence with GGCGCA. Genotyping of two "haplotype tagging" SNPs, C44857T and A44964G, in the Atherosclerosis Risk in Communities (ARIC) study population showed that in Caucasians, but not in African Americans, the inferred TA haplotype had a significant LDL-cholesterol lowering effect. The adjusted LDL-cholesterol levels in the TA/TA diplotypes were lower by 6.10 mg/dl in men (P < 0.001) and by 4.63 mg/dl in women (P < 0.01) than in individuals with other diplotypes. Caucasian men homozygous for CA, in contrast, showed significantly higher LDL-cholesterol (P < 0.04), lower HDL-cholesterol (P < 0.02) and higher LDL/HDL ratios (P < 0.001). Thus our data shows that 3'UTR sequences that cause higher reporter gene expression in vitro are associated in Caucasians with plasma lipid profiles indicative of higher cardiovascular risk, suggesting that further studies of quantitative variants in the LDLR gene will be valuable.
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PMID:Quantitative effects of common genetic variations in the 3'UTR of the human LDL-receptor gene and their associations with plasma lipid levels in the Atherosclerosis Risk in Communities study. 1727 44

HIV protease inhibitors (PIs) have been associated with the serious Metabolic Syndrome, which is the major risk factor of atherosclerotic cardiovascular disease. Atherosclerosis is widely considered to be a chronic inflammatory disease. Macrophages are the most prominent cell type present in atherosclerotic lesions and play essential roles in both early lesion development and late lesion complications. We previously reported that HIV PIs induced accumulation of intracellular free cholesterol and lipids, decreased endoplasmic reticulum (ER) calcium stores, activated the unfolded protein response (UPR), significantly increased apoptosis, and promoted foam cell formation in macrophages. HIV PI-induced ER stress and subsequent activation of the UPR, represents an important cell signaling mechanism of HIV PI-induced metabolic syndromes. Here we show that all HIV PIs, except amprenavir, increased expression of the major mediators of inflammatory response, TNF-alpha and IL-6, to varying degrees. Furthermore, we show that the RNA-binding protein, HuR, plays an important role in HIV PI-induced expression of TNF-alpha and IL-6. Atazanavir increased the cytoplasmic levels of HuR and enhanced the binding of HuR to 3'-UTR of TNF-alpha and IL-6. Down regulation of HuR expression by siRNA prevented atazanavir-induced increase of TNF-alpha and IL-6. These results suggest that HuR might have an impact on pathophysiological processes of HIV PI-induced atherosclerosis.
Atherosclerosis 2007 Nov
PMID:HIV protease inhibitors increase TNF-alpha and IL-6 expression in macrophages: involvement of the RNA-binding protein HuR. 1753 Dec 41

Insulin resistance, as well as vascular disease, both share a relevant genetic background taking the influence of a positive family history of these disorders. On the other hand, insulin resistance is associated with a proatherosclerotic disturbance in nitric oxide dependent vasodilation, probably contributing to the link between these two disorders. We examined the association between nitric oxide dependent vasodilation (measured with high resolution ultrasound at 13 MHz) and three relevant NO-synthase (eNOS)-polymorphisms in 200 insulin resistant subjects participating in the Tuebinger Lifestyle Intervention Program (TULIP). This study revealed that carriers of the eNOS intron 4 polymorphism (aa 2.16%; ab 24.2%; bb 73.2%) show significantly worse endothelial, and thereby eNOS dependent vasodilation (p=0.03, multivariate ANOVA), as compared to wildtype carriers. The 5' UTR T-786C and the G894 T polymorphism did not show any influence on eNOS-activity. In subjects at increased risk to develop type 2 diabetes, the eNOS intron 4 polymorphism is independently associated with endothelial function as indicated by disturbed endothelial NO production. Due to the high prevalence and the relatively strong effect, this polymorphism might help to identify subjects at increased risk for atherosclerosis associated with overweight and insulin resistance.
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PMID:Endothelial NO-synthase intron 4 polymorphism is associated with disturbed in vivo nitric oxide production in individuals prone to type 2 diabetes. 1809 16

The association of polymorphisms affecting lipid metabolism with the risk of myocardial infarction (MI) in type 2 diabetes mellitus was investigated. The Genetics, Outcomes and Lipids in type 2 Diabetes (GOLD) Study is a prospective, multicenter study, conducted on 990 patients presenting diabetes and MI (n=386), or diabetes without previous manifestation of stroke, peripheral or coronary arterial disease (n=604), recruited from 27 institutions in Brazil. APO A1 (A/G -75 and C/T +83) and APO C3 (C/G 3'UTR) non-coding sequences, CETP (Taq 1B), LPL (D9N), APO E (epsilon2, epsilon3, epsilon4,), PON-1 (Q192R), and two LCAT variants Arg(147)-->Trp and Tyr(171)-->Stop were tested by PCR-RFLP. There was a higher prevalence of LPL DN genotype (19% vs.12%, p=0.03) and a higher frequency of the N allele (11% vs. 7%) among subjects with MI when compared to controls, with an odds ratio of MI for carriers of 9N allele of 2.46 (95% CI=1.79-3.39, p<0.0001). This association was present in men and women, in non-smokers and in hypertensive patients. A logistic regression model including gender, duration of diabetes, systolic blood pressure, HDL-C, left ventricle hypertrophy and D9N polymorphism showed that the latter still remained significantly associated with MI (OR=1.50, 95% CI=1.02-2.25, p=0.049). These findings suggest that D9N polymorphism can be a useful risk marker for myocardial infarction and that further potential candidate genes should be screened for exploratory analysis and for future therapeutic intervention in diabetes.
Atherosclerosis 2009 May
PMID:Association of lipoprotein lipase D9N polymorphism with myocardial infarction in type 2 diabetes: the genetics, outcomes, and lipids in type 2 diabetes (GOLD) study. 1882 27

Regulation of angiotensin II type 1 receptor (AT1R) has a pathophysiological role in hypertension, atherosclerosis and heart failure. We started from an observation that the 3'-untranslated region (3'-UTR) of AT1R mRNA suppressed AT1R translation. Using affinity purification for the separation of 3'-UTR-binding proteins and mass spectrometry for their identification, we describe glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an AT1R 3'-UTR-binding protein. RNA electrophoretic mobility shift analysis with purified GAPDH further demonstrated a direct interaction with the 3'-UTR while GAPDH immunoprecipitation confirmed this interaction with endogenous AT1R mRNA. GAPDH-binding site was mapped to 1-100 of 3'-UTR. GAPDH-bound target mRNAs were identified by expression array hybridization. Analysis of secondary structures shared among GAPDH targets led to the identification of a RNA motif rich in adenines and uracils. Silencing of GAPDH increased the expression of both endogenous and transfected AT1R. Similarly, a decrease in GAPDH expression by H(2)O(2) led to an increased level of AT1R expression. Consistent with GAPDH having a central role in H(2)O(2)-mediated AT1R regulation, both the deletion of GAPDH-binding site and GAPDH overexpression attenuated the effect of H(2)O(2) on AT1R mRNA. Taken together, GAPDH is a translational suppressor of AT1R and mediates the effect of H(2)O(2) on AT1R mRNA.
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PMID:Posttranscriptional regulation of angiotensin II type 1 receptor expression by glyceraldehyde 3-phosphate dehydrogenase. 1924 43

HIV protease inhibitor (PI)-associated cardiovascular risk, especially atherosclerosis, has become a major concern in the clinic. Macrophages are key players in the inflammatory response and atherosclerosis formation. We have previously shown that HIV PIs induce endoplasmic reticulum (ER) stress, activate the unfolded protein response (UPR), and increase the synthesis of the inflammatory cytokines, TNF-alpha and IL-6, by regulating the intracellular translocation of RNA binding protein HuR in macrophages. However, the underlying signaling mechanisms remain unclear. We show here that the HIV PI lopinavir significantly activated the extracellular-signal regulated protein kinase (ERK), but not c-Jun N-terminal kinase (JNK) and p38 MAPK. Lopinavir-induced cytosolic translocation of HuR and TNF-alpha and IL-6 synthesis was attenuated by specific chemical inhibitor of MEK (PD98058) or over-expression of dominant negative mutant of MEK1. In addition, we demonstrated that lopinavir-induced ERK activation and TNF-alpha and IL-6 expression were completely inhibited in macrophages from CHOP null mice. Taken together, these results indicate activation of the UPR plays an essential role in HIV PI-induced inflammatory cytokine synthesis and release by activating ERK, which increases the cytosolic translocation of HuR and subsequent binding to the 3'UTR of TNF-alpha and IL-6 mRNAs in macrophages.
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PMID:HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages. 1944 25

Oxidized low-density lipoprotein-receptor 1 (OLR-1) might be involved in the risk of atherosclerosis and its complications. Several studies have been carried out to explore the role of OLR-1 gene polymorphisms in the risk of coronary artery disease. Our study investigated whether the G501C and the 3'UTR C188T polymorphisms of the OLR-1 gene were genetic risk factors of acute coronary syndrome (ACS) in the Han Chinese population. Significant differences were found in genotype frequencies of the OLR-1 G501C polymorphism between 198 ACS patients and 204 control individuals. The CC genotype frequency in the ACS group was significantly higher than that in the control group (5.6% and 1.5% in ACS patients and control subjects, respectively), and the p-value and odds ratio were 0.028 and 3.911, respectively. Using the CC genotype as a reference, we have shown a significant association between carriers of the G allele (GG + GC genotypes) and a decreased risk of ACS (p = 0.026, odds ratio = 0.254, 95% confidence interval = 0.070-0.924). The OLR-1 G501C polymorphism might be associated with ACS in the Han Chinese population.
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PMID:The G501C polymorphism of the oxidized low-density lipoprotein-receptor 1 gene is associated with acute coronary syndrome in the Han Chinese population. 2013 18

Sesame lignans have antioxidative and anti-inflammatory properties. We focused on the effects of the lignans sesamin and sesamol on the expression of endothelial-leukocyte adhesion molecules in tumor necrosis factor-alpha (TNF-alpha)-treated human aortic endothelial cells (HAECs). When HAECs were pretreated with sesamin (10 or 100 microM), the TNF-alpha-induced expression of intercellular cell adhesion molecule-1 (ICAM-1) was significantly reduced (35 or 70% decrease, respectively) by Western blotting. Sesamol was less effective at inhibiting ICAM-1 expression (30% decrease at 100 microM). Sesamin and sesamol reduced the marked TNF-alpha-induced increase in human antigen R (HuR) translocation and the interaction between HuR and the 3'UTR of ICAM-1 mRNA. Both significantly reduced the binding of monocytes to TNF-alpha-stimulated HAECs. Sesamin significantly attenuated TNF-alpha-induced ICAM-1 expression and cell adhesion by downregulation of extracellular signal-regulated kinase 1/2 and p38. Furthermore, in vivo, sesamin attenuated intimal thickening and ICAM-1 expression seen in aortas of apolipoprotein-E-deficient mice. Taken together, these data suggest that sesamin inhibits TNF-alpha-induced extracellular signal-regulated kinase/p38 phosphorylation, nuclear translocation of NF-kappaB p65, cytoplasmic translocalization of HuR and thereby suppresses ICAM-1 expression, resulting in reduced adhesion of leukocytes. These results also suggest that sesamin may prevent the development of atherosclerosis and inflammatory responses.
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PMID:Sesamin attenuates intercellular cell adhesion molecule-1 expression in vitro in TNF-alpha-treated human aortic endothelial cells and in vivo in apolipoprotein-E-deficient mice. 2030 75


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