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 peroxisome-proliferator-activated receptor gamma is a member of the nuclear receptor superfamily that functions as a key transcriptional regulator of cell differentiation and lipid metabolism. In addition, peroxisome-proliferator-activated receptor gamma is now recognized to be the biological receptor for the thiazolidinedione class of antidiabetic drugs, which includes troglitazone and rosiglitazone. Recent evidence indicates that peroxisome-proliferator-activated receptor gamma is expressed at high levels in macrophages, including the foam cells of atherosclerotic lesions. Oxidized low-density lipoprotein, which plays a central role in lesion development, can activate peroxisome-proliferator-activated receptor gamma by providing the cell with oxidized fatty acid ligands of the receptor. The elucidation of a peroxisome-proliferator-activated receptor gamma signalling pathway in macrophages provides a mechanism by which oxidized lipids may directly regulate gene expression in the context of the atherosclerotic lesions. A number of potential target genes for peroxisome-proliferator-activated receptor gamma in these cells have been identified. Some, such as the type B scavenger receptor CD36 are induced by peroxisome-proliferator-activated receptor gamma ligands, whereas others, such as scavenger receptor type A, inducible nitric oxide synthetase and certain cytokines, are repressed. Given the widespread clinical use of thiazolidinediones, it is important to consider the influence of these drugs on the risk of atherosclerosis. The net effect of peroxisome-proliferator-activated receptor gamma ligands on the atherogenic process is likely to reflect a balance between local effects in the artery wall and systemic effects on lipid metabolism.
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PMID:Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor gamma: implications for cardiovascular disease. 1068 41

Triglyceride-rich remnant lipoproteins are considered as major risk factors contributing to the pathogenesis of atherosclerosis. Because apolipoprotein (apo) C-III is a major determinant of plasma triglyceride and remnant lipoprotein metabolism, it is important to understand how the expression of this gene is regulated. In the present study, we identified the orphan nuclear receptor RORalpha1 as a regulator of human and mouse apo C-III gene expression. Plasma triglyceride and apo C-III protein concentrations in staggerer (sg/sg) mice, homozygous for a deletion in the RORalpha gene, were significantly lower than in wild type littermates. The lowered plasma apo C-III levels were associated with reduced apo C-III mRNA levels in liver and intestine of sg/sg mice. Transient transfection experiments in human hepatoma HepG2, human colonic CaCO2, and rabbit kidney RK13 cells demonstrated that overexpression of the human RORalpha1 isoform specifically increases human apo C-III promoter activity, indicating that RORalpha1 enhances human apo C-III gene transcription. RORalpha1 response elements were mapped by promoter deletion analysis and gel shift experiments to two AGGTCA half-sites located at positions -83/-78 (within the C3P site) and -23/-18 (downstream of the TATA box) in the human apo C-III promoter, with the -23/-18 site exhibiting the highest binding affinity. Transfection of site-directed mutated constructs in HepG2 cells indicated that the RORalpha1 effect is predominantly mediated by the -23/-18 site. This site is conserved in the mouse apo C-III gene promoter. Moreover, RORalpha binds to the equivalent mouse site and activates constructs containing three copies of the mouse site cloned in front of an heterologous promoter. Taken together, our data identify RORalpha as a transcriptional regulator of apo C-III gene expression, providing a novel, physiological role for RORalpha1 in the regulation of genes controlling triglyceride metabolism.
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PMID:Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha. 1105 33

The serum level of high-density lipoprotein cholesterol (HDL-c), which protects against the development of atherosclerosis, is under genetic control. However, the genetic components responsible for the serum HDL-c level are yet to be determined. A recent knockout mouse study demonstrated that hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is an essential transcriptional regulator of HDL-c metabolism. In this study, the association of an HNF-1 alpha gene polymorphism, isoleucine (Ile) 27 leucine (Leu), with lipid parameters, in particular with serum HDL-c level, was studied in 356 unrelated Japanese men. Though no significant difference was observed in total cholesterol and triglyceride levels among the three genotypes, the serum HDL-c level was significantly associated with the genotype (P < 0.01, trend test). Subjects with the Ile/Ile genotype had low serum HDL-c levels, and those with the Leu/Leu genotype had high serum HDL-c levels. These results demonstrate that the HNF-1 alpha gene locus is associated with serum HDL-c level and suggest that the Ile27 allele is a risk marker for atherosclerosis.
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PMID:Association of I27L polymorphism of hepatocyte nuclear factor-1 alpha gene with high-density lipoprotein cholesterol level. 1278 52

Activation of vascular smooth muscle cells (SMCs) by platelet-derived growth factor (PDGF) is a seminal event in the initiation and progression of the atherosclerotic lesion and may contribute to atherosclerotic plaque instability with plaque rupture and thrombus formation. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play a major role in thrombus formation after plaque rupture. This study examined intracellular signaling pathways leading to TF expression and Egr-1 activation, a key element in tissue factor transcription, by PDGF-BB in rat SMCs. PDGF-BB induced TF mRNA and protein expression in a time-dependent manner. Early growth response factor-1 (Egr-1) binding activity was also induced by PDGF-BB, as well as phosphorylation of extracellular signal-regulated kinase. PDGF-BB-induced Egr-1 activation was suppressed by inhibitors of 2 upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and Src family kinases, whereas antioxidants, phosphatidylinositol 3-phosphate kinase, and p38 MAPK inhibitors had no effect. PDGF-BB-stimulated expression of the transcriptional co-repressor NAB2 was time-dependent. Furthermore, transient transfections of SMCs with wild-type and mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of PDGF-BB-induced TF expression. Taken together, the results suggest that PDGF-BB induces TF expression and activity in SMC by a Src family kinases/ERK/Egr-1 signaling pathway and may therefore contribute to thrombus formation in advanced atherosclerosis and restenosis.
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PMID:Platelet-derived growth factor induces tissue factor expression in vascular smooth muscle cells via activation of Egr-1. 1549 29

Vitamin E has the ability to scavenge a wide spectrum of free radicals, including singlet oxygen, superoxide, and hydroxyl radicals. It has beneficial effects against several other disorders, such as atherosclerosis and ischemic heart disease, because it acts as a transcriptional regulator for gene expression via a transcription factor TAP. The beneficial effect of vitamin E on plasma insulin and glucagon levels was examined using radioimmunoassay technique. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin at a dose of 60 mg/kg body weight. Vitamin E was given at a dose of either 0.2 mg, 0.4 mg, or 0.8 mg per animal 10 days before and after the onset of diabetes. Vitamin E significantly (P < 0.05) increased plasma insulin levels in normal rats but failed to increase the plasma insulin level in diabetic rats. In contrast, vitamin E caused a significant (P < 0.05) reduction in plasma glucagon level in rats treated before and after the onset of diabetes. Vitamin E may ameliorate some diabetic complication via reduction in the level of circulating glucagon.
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PMID:Vitamin E decreases the hyperglucagonemia of diabetic rats. 1715 20

The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African-, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.
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PMID:A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression. 1751 56

The clustering of cardiovascular risk factors associated with the metabolic syndrome and type 2 diabetes suggests central mechanisms may exist that account for the presence of these abnormalities. Likewise, this clustering also suggests that key therapeutic targets may exist that could allow improvements in many of these parameters. Extensive data implicate peroxisome proliferator-activated receptor-alpha (PPARalpha) as an important transcriptional regulator of lipid metabolism, energy balance and inflammation. PPARalpha is also an established drug target. Experimental data show that activation of PPARalpha by agonists such as fenofibrate improves dyslipidaemia, increases cholesterol efflux and limits inflammation. All of these effects would also be predicted to decrease atherosclerotic risk. Evidence from surrogate markers in humans is also supportive of the concept that PPARalpha may act as a central target capable of influencing a variety of different pathways involved in lipid metabolism. Thus, fenofibrate offers the potential for inducing a co-ordinated PPARalpha response that may improve dyslipidaemia, repress inflammation and limit atherosclerosis in patients with the metabolic syndrome or type 2 diabetes.
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PMID:Preventing type 2 diabetes and cardiovascular disease in metabolic syndrome: the role of PPARalpha. 1793 55

Oleogum resin (known as guggul) from the guggul tree, Commiphora mukul, found in India, Bangladesh, and Pakistan, has been used to treat various diseases including hyper-cholesterolemia, atherosclerosis, rheumatism, and obesity over several thousands of years. Guggulsterone isolated from guggul has been identified as the bioactive constituent responsible for guggul's therapeutic effects. Since the first study demonstrating the therapeutic effects of guggul in an animal model in 1966, numerous preclinical and clinical trails have been carried out. Although differences in study design, methodological quality, statistical analysis, sample size, and subject population result in certain inconsistencies in the response to therapy, the cumulative data from in vitro, preclinical, and clinical studies largely support the therapeutic claims for guggul described in the ancient Ayurvedic text. However, future clinical studies with much larger size and longer term are required to confirm these claims. The cardiovascular benefits of the therapy are derived from the multiple pharmacological activities associated with guggul or guggulsterone, notably its hypolipidemic, antioxidant, and antiinflammatory activities. It has been established that guggulsterone is an antagonist at farnesoid x receptor (FXR), a key transcriptional regulator for the maintenance of cholesterol and bile acid homeostasis. The FXR antagonism by guggulsterone has been proposed as a mechanism for its hypolipidemic effect. A recent study demonstrates that guggulsterone upregulates the bile salt export pump (BSEP), an efflux transporter responsible for removal of cholesterol metabolites, bile acids from the liver. Such upregulation of BSEP expression by guggulsterone favors cholesterol metabolism into bile acids, and thus represents another possible mechanism for its hypolipidemic activity. Guggulsterone has been found to potently inhibit the activation of nuclear factor-kappaB (NF-kappaB), a critical regulator of inflammatory responses. Such repression of NF-kappaB activation by guggulsterone has been proposed as a mechanism of the antiinflammatory effect of guggulsterone.
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PMID:Therapeutic effects of guggul and its constituent guggulsterone: cardiovascular benefits. 1807 36

The peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. To date, three different PPAR isotypes, namely PPAR-alpha, -delta, and -gamma, have been identified in vertebrates and have distinct patterns of tissue distribution. Like all nuclear receptors, the human PPAR-gamma (hPPAR-gamma) is characterized by a modular structure composed of an N-terminal A/B domain, a DNA-binding domain with two zinc fingers (C domain), a D domain, and a C-terminal ligand-binding domain (E/F domain). Human PPAR-gamma exists in two protein isoforms, hPPAR-gamma(1) and -gamma(2), with different lengths of the N-terminal. The hPPAR-gamma(2) isoform is predominantly expressed in adipose tissue, whereas hPPAR-gamma(1) is relatively widely expressed. Human PPAR-gamma plays a critical physiological role as a central transcriptional regulator of both adipogenic and lipogenic programs. Its transcriptional activity is induced by the binding of endogenous and synthetic lipophilic ligands, which has led to the determination of many roles for PPAR-gamma in pathological states such as type 2 diabetes, atherosclerosis, inflammation, and cancer. Of the synthetic ligands, the thiazolidinedione class of insulin-sensitizing drugs (ciglitazone, pioglitazone, troglitazone, rosiglitazone) is employed clinically in patients with type 2 diabetes.
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PMID:Structure and physiological functions of the human peroxisome proliferator-activated receptor gamma. 1883 59

Asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is recently defined as an independent cardiovascular risk factor. Tissue factor (TF) expression and procoagulant activity (PCA) of peripheral monocytes are increased in patients with acute coronary syndromes (ACS), which resulted in blood procoagulant state tending to thrombus formation. In the present study, we tested the hypothesis that ADMA contribute to TF expression of peripheral monocytes in ACS. Twenty patients with unstable angina (UA), 20 patients with stable angina (SA) and 20 control subjects were recruited. Monocytic cell line THP-1 was incubated with different concentrations of ADMA (1-10microM) for various periods (6-24h). Our results showed that plasma level of ADMA in patients with UA was significantly higher than those in patients with SA or in the control group, and positively correlated with TF antigen level and PCA of circulating monocytes. Adjusting for all patient characteristics, we confirmed these findings in multivariate regression analyses. In cultured THP-1 cells, ADMA transcriptionally upregulated both TF antigen expression and PCA in a concentration-dependent manner. The experiments using nuclear factor-kappaB (NF-kappaB) inhibitor and transient transfection with wild-type and mutated TF promotor constructs showed that the NF-kappaB is an important transcriptional regulator of ADMA-induced TF expression. Our results suggest that elevated plasma level of ADMA induces TF expression in monocytes via NF-kappaB-dependent pathway, which contributes to procoagulant phenotype of circulating monocytes in ACS.
Atherosclerosis 2009 Aug
PMID:Asymmetric dimethylarginine induces tissue factor expression in monocytes via NF-kappaB-dependent pathway: Role in acute coronary syndromes. 1916 13


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