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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two specific endothelial cell products, von Willebrand factor and soluble E-selectin, were measured together with serum lipids, lipoprotein(a), systolic and diastolic blood pressure (SHP, DBP) in a follow up study of 162 patients attending a dedicated lipid clinic. Patients were further classified by the presence or absence of symptomatic vascular disease and smoking. After a mean of 49 months, 45 patients experienced a cardiovascular event (fatal or nonfatal myocardial infarction, stroke, or arterial surgery) and 11 developed non-cardiovascular diseases, including cancer. In univariate analysis, existing vascular disease (P < 0.01), increased levels of von Willebrand factor (P < 0.0001) and low density lipoprotein cholesterol (P < 0.02), greater age (P < 0.01), and lower levels of soluble E-selectin (P < 0.03) were all predictive of future vascular events. However, in multivariate analysis, only increased von Willebrand factor was predictive (P < 0.001). von Willebrand factor was also higher in patients who developed non-cardiovascular disease relative to those free of disease (P < 0.05). Our data support the hypothesis that increased levels of von Willebrand factor are an indicator of poor prognosis in patients with atherosclerosis or its risk factors.
Atherosclerosis 1997 Jul 25
PMID:von Willebrand factor and soluble E-selectin in the prediction of cardiovascular disease progression in hyperlipidaemia. 924 60

Recent advances in molecular biology have greatly accelerated knowledge relating to the significance of the enterohepatic circulation of bile salts. This review highlights the role that both oxysterols and bile salts play as ligands which, when bound to nuclear hormone receptors, activate transcription factors that set into play feed-forward catabolism of cholesterol to bile salts and feedback control of bile acid synthesis. The nuclear hormone receptors, liver X receptor (LXR) and farnesoid X receptor (FXR) both combined as heterodimers with retinoid X receptor and with oxysterols and bile salts, respectively as their ligands, initiate powerful genetic controls over cholesterol and bile acid homeostatic mechanisms. LXR/RXR signals molecular control of feed-forward catabolism of cholesterol to bile acids while FXR/RXR initiates feedback control of bile acid synthesis. An additional nuclear hormone receptor, small heterodimer partner (SHP), is required to inhibit the competence factor, liver receptor homolog-1 to achieve repression of bile acid synthesis in the liver and in so doing SHP autoregulates its own function. Additionally, while bile acid synthesis is repressed, pool size is preserved by the action of FXR/RXR at both hepatic and intestinal levels, which genetically signals enhanced hepatocyte bile salt transport by the bile salt export pump (BSEP) and the ileal bile acid binding protein (IBABP) for ileal reabsorption. During activation of cholesterol catabolism, LXR/RXR enhances reverse cholesterol transport by increasing cholesterol efflux via the ABC-1 transporter from extrahepatic cells. This cholesterol is then taken up by high-density lipoprotein (HDL) and transported back to the liver for further cholesterol catabolism and elimination in bile. The genetic coordination of nuclear hormone receptor function within the territory of the enterohepatic of bile salts allows for normal cholesterol and bile acid homeostasis thereby preventing atherosclerosis.
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PMID:The coming of age of our understanding of the enterohepatic circulation of bile salts. 1255 50

Blocking intestinal bile acid absorption by inhibiting the apical sodium codependent bile acid transporter (ASBT) is a target for increasing hepatic bile acid synthesis and reducing plasma LDL cholesterol. SC-435 was identified as a potent inhibitor of ASBT (IC50 = 1.5 nM) in cells transfected with the human ASBT gene. Dietary administration of 3 mg/kg to 30 mg/kg SC-435 to apolipoprotein E-/- (apoE-/-) mice increased fecal bile acid excretion by >2.5-fold. In vivo inhibition of ASBT also resulted in significant increases of hepatic mRNA levels for cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Administration of 10 mg/kg SC-435 for 12 weeks to apoE-/- mice lowered serum total cholesterol by 35% and reduced aortic root lesion area by 65%. Treatment of apoE-/- mice also resulted in decreased expression of ileal bile acid binding protein and hepatic nuclear hormone receptor small heterodimer partner, direct target genes of the farnesoid X receptor (FXR), suggesting a possible role of FXR in SC-435 modulation of cholesterol homeostasis. In dogs, SC-435 treatment reduced serum total cholesterol levels by </=12% and, in combination with atorvastatin treatment, caused an additional reduction of 25%. These results suggest that specific inhibition of ASBT is a novel therapeutic approach for treatment of hypercholesterolemia resulting in a decreased risk for atherosclerosis.
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PMID:Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435. 1281 Aug 16

The nuclear receptors liver X receptor (LXR) alpha and farnesoid X receptor (FXR) are positive and negative regulators of cholesterol 7alpha-hydroxylase (CYP7A1) transcription, respectively. To clarify their roles in the regulation of CYP7A1 in mice, we investigated mRNA expression of their target genes in the livers of C57BL/6 mice fed the following five diets for 2 weeks: a standard diet, cholic acid, cholesterol, cholesterol+high fat, or an atherogenic diet (cholic acid+cholesterol+high fat). The mRNA level of ATP-binding cassette transporter (ABC) A1 gene, one of LXRalpha target genes, significantly increased on the diets containing cholic acid and/or cholesterol+high fat, but not on the diet containing cholesterol alone. On the other hand, the mRNA levels of the FXR target genes ABCB11, ABCC2, and short heterodimer partner increased only on the diet containing cholic acid with or without cholesterol+high fat. Surprisingly, cholesterol alone or cholesterol+high fat did not affect CYP7A1 mRNA level, whereas cholic acid with or without cholesterol+high fat greatly reduced the level. Thus, in the atherogenic diet-fed mice, cholic acid component is needed for the FXR activation, and FXR dominantly regulates CYP7A1 transcription.
Atherosclerosis 2005 Feb
PMID:Regulation of cholesterol 7alpha-hydroxylase mRNA expression in C57BL/6 mice fed an atherogenic diet. 1569 33

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 therapeutic utility of liver X receptor (LXR) agonists in treating atherosclerosis is limited by an undesired accumulation of triglycerides in the blood and liver. This effect is caused by an increase in the transcription of genes involved in fatty acid synthesis. Here, we show that the primary bile acid, chenodeoxycholic acid (CDCA), antagonizes the stimulatory effect of the synthetic LXR agonist, T0-901317, on the expression of acetyl-coenzyme A carboxylase-alpha (ACCalpha) and other lipogenic enzymes in chick embryo hepatocyte cultures. CDCA inhibits T0-901317-induced ACCalpha transcription by suppressing the enhancer activity of a LXR response unit (-101 to -71 bp) that binds LXR and sterol-regulatory element binding protein-1 (SREBP-1). We also demonstrate that CDCA decreases the expression of SREBP-1 in the nucleus and the acetylation of histone H3 and H4 at the ACCalpha LXR response unit. The CDCA-mediated reduction in ACCalpha expression is associated with a decrease in the expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and small heterodimer partner and an increase in the expression of fibroblast growth factor-19 (FGF-19). Ectopic expression of FGF-19 decreases T0-901317-induced ACCalpha expression. Inhibition of p38 mitogen-activated protein kinase (MAPK) and/or extracellular signal-regulated kinase (ERK) suppresses the effects of CDCA on the expression of ACCalpha, SREBP-1, PGC-1alpha, and FGF-19. These results demonstrate that CDCA inhibits T0-901317-induced ACCalpha transcription by suppressing the activity of LXR and SREBP-1. We postulate that p38 MAPK, ERK, PGC-1alpha, and FGF-19 are components of the signaling pathway(s) mediating the regulation of ACCalpha gene transcription by CDCA.
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PMID:Chenodeoxycholic acid suppresses the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317. 1782 58

Multiple studies suggest increased conversion of cholesterol to bile acids by cholesterol 7alpha-hydroxylase (CYP7A1) protects against dyslipidemia and atherosclerosis. CYP7A1 expression is repressed by the sequential activity of two nuclear hormone receptors, farnesoid X receptor (FXR) and small heterodimer partner (SHP). Here we demonstrate 129 strain SHP(-/-) mice are protected against hypercholesterolemia resulting from either a cholesterol/cholic acid (chol/CA) diet or from hypothyroidism. In a mixed 129-C57Bl/6 background, LDLR(-/-) and LDLR(-/-)SHP(-/-) mice had nearly identical elevations in hepatic cholesterol content and repression of cholesterol regulated genes when fed a Western diet. However, the LDLR(-/-)SHP(-/-) mice had greatly reduced elevations in serum VLDL and LDL cholesterol levels and triglyceride (TG) levels as compared with LDLR(-/-) mice. Additionally, the hepatic inflammation produced by the Western diet in the LDLR(-/-) mice was abolished in the LDLR(-/-)SHP(-/-) mice. CYP7A1 expression was induced 10-fold by the Western diet in the LDLR(-/-)SHP(-/-) mice but not in the LDLR(-/-) mice. Finally, hepatocyte-specific deletion of SHP expression was also protective against dyslipidemia induced by either a chol/CA diet or by hypothyroidism. While no antagonist ligands have yet been identified for SHP, these results suggest selective inhibition of hepatic SHP expression may provide protection against dyslipidemia.
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PMID:Loss of small heterodimer partner expression in the liver protects against dyslipidemia. 1882 Feb 41

The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. Here, LDL receptor (LDLR(-/-)) or apolipoprotein E (apoE(-/-)) female or male mice were fed a Western diet and treated with a potent synthetic FXR agonist, WAY-362450. Activation of FXR blocked diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation. WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12 alpha-hydroxylase (CYP8B1) expression. To determine if SHP was essential for these protective activities, LDLR(-/-)SHP(-/-) and apoE(-/-)SHP(-/-) mice were similarly treated with WAY-362450. Surprisingly, a notable sex difference was observed in these mice. In male LDLR(-/-)SHP(-/-) or apoE(-/-)SHP(-/-) mice, WAY-362450 still repressed CYP7A1 and CYP8B1 expression by 10-fold and still strongly reduced non-HDL cholesterol levels and aortic lesion area. In contrast, in the female LDLR(-/-)SHP(-/-) or apoE(-/-)SHP(-/-) mice, WAY-362450 only slightly repressed CYP7A1 and CYP8B1 expression and did not reduce non-HDL cholesterol or aortic lesion size. WAY-362450 inhibition of hypertriglyceridemia remained intact in LDLR(-/-) or apoE(-/-) mice lacking SHP of both sexes. These results suggest that activation of FXR protects against atherosclerosis in the mouse, and this protective effect correlates with repression of bile acid synthetic genes, with mechanistic differences between male and female mice.
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PMID:Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. 1917 69

Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-beta signaling pathways. Here, we investigated whether SHP inhibited angiotensin II-stimulated PAI-1 expression in VSMCs. Adenovirus-mediated overexpression of SHP (Ad- SHP) in VSMCs inhibited angiotensin II- and TGF-beta-stimulated PAI-1 expression. Ad-SHP also inhibited angiotensin II-, TGF-beta- and Smad3-stimulated PAI-1 promoter activity, and angiotensin II-stimulated AP-1 activity. The level of PAI-1 expression was significantly higher in VSMCs of SHP(-/-) mice than wild type mice. Moreover, loss of SHP increased PAI-1 mRNA expression after angiotensin II treatment. These results suggest that SHP inhibits PAI-1 expression in VSMCs through the suppression of TGF-beta/Smad3 and AP-1 activity. Thus, agents that target the induction of SHP expression in VSMCs might help prevent the development and progression of atherosclerosis.
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PMID:Orphan nuclear receptor small heterodimer partner inhibits angiotensin II- stimulated PAI-1 expression in vascular smooth muscle cells. 1988 97

Atherosclerosis is the leading cause of illness and death. Therapeutic strategies aimed at reducing cholesterol plasma levels have shown efficacy in either reducing progression of atherosclerotic plaques and atherosclerosis-related mortality. The farnesoid-X-receptor (FXR) is a member of metabolic nuclear receptors (NRs) superfamily activated by bile acids. In entero-hepatic tissues, FXR functions as a bile acid sensor regulating bile acid synthesis, detoxification and excretion. In the liver FXR induces the expression of an atypical NR, the small heterodimer partner, which subsequently inhibits the activity of hepatocyte nuclear factor 4alpha repressing the transcription of cholesterol 7a-hydroxylase, the critical regulatory gene in bile acid synthesis. In the intestine FXR induces the release of fibroblast growth factor 15 (FGF15) (or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signalling to inhibit bile acid synthesis. In rodents, FXR activation decreases bile acid synthesis and lipogenesis and increases lipoprotein clearance, and regulates glucose homeostasis by reducing liver gluconeogenesis. FXR exerts counter-regulatory effects on macrophages, vascular smooth muscle cells and endothelial cells. FXR deficiency in mice results in a pro-atherogenetic lipoproteins profile and insulin resistance but FXR(-/-) mice fail to develop any detectable plaques on high-fat diet. Synthetic FXR agonists protect against development of aortic plaques formation in murine models characterized by pro-atherogenetic lipoprotein profile and accelerated atherosclerosis, but reduce HDL levels. Because human and mouse lipoprotein metabolism is modulated by different regulatory pathways the potential drawbacks of FXR ligands on HDL and bile acid synthesis need to addressed in relevant clinical settings.
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PMID:FXR an emerging therapeutic target for the treatment of atherosclerosis. 2004 71


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