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)

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated an important interaction between nuclear factor-kappaB (NF-kappaB) activation and homocysteine (Hcy)-induced chemokine expression in vascular smooth muscle cells and macrophages. The objective of the present study was to investigate the in vivo effect of hyperhomocysteinemia on NF-kappaB activation and the underlying mechanism of Hcy-induced NF-kappaB activation in endothelial cells. Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-kappaB and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. The underlying mechanism of Hcy-induced NF-kappaB activation was investigated in human umbilical cord vein endothelial cells and in human aortic endothelial cells. Incubation of cells with Hcy (100 micromol/L) activated IkappaB kinases (IKKalpha and IKKbeta), leading to phosphorylation and subsequent degradation of IkappaBalpha. As a consequence, NF-kappaB nuclear translocation, enhanced NF-kappaB/DNA binding activity, and increased transcriptional activity occurred. Additional analysis revealed a marked elevation of superoxide anion levels in Hcy-treated cells. Treatment of cells with a superoxide anion scavenger (polyethylene glycol-superoxide dismutase) or IkappaB kinase inhibitor (prostaglandin A(1)) could prevent Hcy-induced activation of IKK kinases and NF-kappaB in endothelial cells. In conclusion, these results suggest that Hcy-induced superoxide anion production may play a potential role for NF-kappaB activation in the early stages of atherosclerosis in the vascular wall via activation of IkappaB kinases.
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PMID:Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress. 1463 Jul 27

Chylomicron remnants, major lipoproteins at postprandial hyperlipidemia, have been considered to be proatherogenic lipoproteins. However, the mechanisms by which chylomicron remnants enhance atherosclerosis have not been fully understood. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine which stimulates migration of monocytes and plays a critical role in the development of atherosclerosis. In this study, we investigated the effect of chylomicron remnants on MCP-1 expression in cultured vascular smooth muscle cells (VSMCs). We prepared chylomicrons from the lymph of gastrostomized rats fed with egg solution and obtained chylomicron remnants from the plasma of hepatectomized rats which were injected with chylomicrons. Treatment of VSMC with chylomicron remnants resulted in a significant increase of the expression of MCP-1 mRNA and protein in a time-and a dose-dependent manner. Further, chylomicron remnants activated p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK1/2). Pretreatment of VSMCs with p38 MAPK inhibitors, SB203580 and SB202190, resulted in a dose-dependent inhibition of chylomicron remnants-induced MCP-1 mRNA and protein expression, whereas a MAPK kinase inhibitor, PD98059, had no effect on these responses. MCP-1 secretion by chylomicron remnants was much more pronounced than those by chylomicrons, oxidized low-density lipoproteins, or lysophosphatidylcholine. These results indicated that chylomicron remnants stimulated MCP-1 expression in VSMCs, and suggested that chylomicron remnants might contribute to the formation of atherosclerosis through this proinflammatory effect.
Atherosclerosis 2003 Dec
PMID:Chylomicron remnants induce monocyte chemoattractant protein-1 expression via p38 MAPK activation in vascular smooth muscle cells. 1464 87

Emerging evidence supports a role for platelets in the progression of atherosclerosis in addition to an involvement in thrombotic vascular occlusion. Platelet Factor 4 (PF4), a chemokine released by activated platelets, stimulates several pro-atherogenic processes. Therefore, we examined the localization of PF4 and the homologous protein, Neutrophil Activating Protein-2 (NAP-2) in lesions representing the evolution of human atherosclerotic plaques. Carotid plaques from 132 patients with critical carotid stenosis and 6 autopsy specimens were studied. Clinical, histologic and immunohistochemical data were analyzed using a chi(2)-test. PF4 was detected in the cytoplasm of luminal and neovascular endothelium, in macrophages and in regions of plaque calcification. The presence of PF4 in macrophages and neovascular endothelium correlated with lesion grade (p = 0.004; p = 0.044). Staining of macrophages for PF4 correlated with the presence of symptomatic atherosclerotic disease (p = 0.028). In early lesions, PF4 was commonly found in macrophages of early lesions (Grade I/II), whereas NAP-2 was rarely present. In conclusion, correlation between PF4 deposition, lesion severity and symptomatic atherosclerosis suggests that persistent platelet activation may contribute to the evolution of atherosclerotic vascular lesions. These studies support the rationale for the chronic use of anti-platelet therapy in patients at risk for developing symptomatic atherosclerosis.
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PMID:Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters. 1465 24

Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a chemokine pathway in vivo with the CC chemokine antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major chemokines and chemokine receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC chemokine or its receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a chemokine receptor antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease.
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PMID:Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. 1465 31

Despite many advances in cardiology, atherosclerosis remains a major medical problem. This is especially the case for individuals with insulin resistance and type 2 diabetes mellitus. Atherosclerotic lesions can develop as early as the second decade of life and progress into clinical disease over time. Atherosclerosis is a complex disorder, involving many cell types and circulating mediators and resulting in an inflammatory state. The control of transcription of inflammatory mediators via ligands for peroxisome proliferator-activated receptor-gamma, such as thiazolidinediones (TZDs), has been raised as a possible mechanism for improving atherosclerosis. Results of studies performed in vitro and in animal models suggest that TZDs may increase cholesterol efflux from macrophages, decrease cytokine expression, and limit chemokine levels. Such effects may underlie the decreases in atherosclerosis seen in mouse models of atherosclerosis after TZD treatment. The direct actions of the TZDs on atherosclerosis may couple with their effects on metabolic parameters through increased insulin sensitivity. Ongoing clinical trials evaluating cardiovascular end points with TZD therapy should provide insight into these possibilities.
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PMID:The vascular biology of atherosclerosis. 1467 67

We have investigated serum chemokines for their suitability as markers of atherosclerosis development in apoE (apolipoprotein E)-deficient ((-/-)) mice. Female C3H apoE(-/-) and C57BL apoE(-/-) mice were fed on either diet W (Western diet; 6 weeks) or normal rodent diet (12 weeks). Serum lipids (0, 6 and 12 weeks) and terminal chemokine levels were measured using commercially available assays, whereas the lesion area was determined using Oil-Red O-stained aortic sections. Serum lipids were higher in C3H apoE(-/-) mice for both diets throughout the study; however, lesions were significantly larger in C57BL apoE(-/-) mice fed on either diet. Chemokine levels were significantly lower in C3H apoE(-/-) mice fed on the normal diet, but no difference was observed between the two groups fed on diet W. We conclude that serum chemokine levels are potential markers for atherosclerosis susceptibility in C3H and C57BL apoE(-/-) mice fed on a normal rodent diet.
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PMID:Circulating levels of the chemokines JE and KC in female C3H apolipoprotein-E-deficient and C57BL apolipoprotein-E-deficient mice as potential markers of atherosclerosis development. 1474 30

Platelets are the most abundant blood source of CD40L, a proinflammatory and prothrombotic costimulatory molecule implicated in atherosclerosis. Agonist stimulation results in the secretion of a soluble form of CD40L (sCD40L) and GP IIb/IIIa receptor inhibition blocks secretion of sCD40L in vitro. However, the effect of GP IIb/IIIa inhibition on sCD40L levels in humans is unknown. Plasma sCD40L and inflammatory markers were measured (t = 0, 0.5, 2, and 24 hr post-PCI) in a cohort of patients receiving abciximab (n = 15), eptifibatide (n = 15), or no GP IIb/IIIa inhibitor (n = 15). PCI in the absence of GP IIb/IIIa inhibitor was associated with a small but measurable rise in sCD40L and the platelet-derived chemokine RANTES. In contrast, eptifibatide significantly lowered baseline sCD40L (P = 0.018) and RANTES (P = 0.006) levels. This effect was not observed with abciximab. GP IIb/IIIa inhibition with eptifibatide lowers levels of sCD40L and RANTES post-stenting, possibly conferring anti-inflammatory as well as antithrombotic effects.
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PMID:GP IIb/IIIa inhibition with eptifibatide lowers levels of soluble CD40L and RANTES after percutaneous coronary intervention. 1475 9

Allograft arteriopathy is a vascular intimal proliferative process that occurs in all solid organ transplants and stands as the single most significant obstacle to successful long-term solid organ transplantation; it shares a number of pathologic features with restenosis lesions and atherosclerosis. This article will review some of the newer developments in our understanding of the immunological and vascular biology underpinnings of the disease, including the roles played by cytokine and chemokine mediators in recruiting and activating both inflammatory cells, as well as smooth muscle cell precursors.
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PMID:Allograft arteriopathy: pathogenesis update. 1476 83

Leukocyte recruitment is crucial for the response to vascular injury in spontaneous and accelerated atherosclerosis. Whereas the mechanisms of leukocyte adhesion to endothelium or matrix-bound platelets have been characterized, less is known about the proadhesive role of smooth muscle cells (SMCs) exposed after endothelial denudation. In laminar flow assays, neointimal rat SMCs (niSMCs) supported a 2.5-fold higher arrest of monocytes and "memory" T lymphocytes than medial SMCs, which was dependent on both P-selectin and VLA-4, as demonstrated by blocking antibodies. The increase in monocyte arrest on niSMCs was triggered by the CXC chemokine GRO-alpha and fractalkine, whereas "memory" T cell arrest was mediated by stromal cell-derived factor (SDF)-1alpha. This functional phenotype was paralleled by a constitutively increased mRNA and surface expression of P-selectin and of relevant chemokines in niSMCs, as assessed by real-time PCR and flow cytometry. The increased expression of P-selectin in niSMCs versus medial SMCs was associated with enhanced NF-kappaB activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-kappaB by adenoviral IkappaBalpha in niSMCs resulted in a marked reduction of increased leukocyte arrest in flow. Furthermore, P-selectin expression by niSMCs in vivo was confirmed in a hypercholesterolemic mouse model of vascular injury by double immunofluorescence and by RT-PCR after laser microdissection. In conclusion, we have identified a NF-kappaB-mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.
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PMID:Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines. 1505 39

The infection and inflammation process is associated with disturbances in lipid and lipoprotein metabolism. The apolipoprotein E (apo E) plays an important role in the lipoprotein metabolism and has been linked to inflammatory disease such as atherosclerosis and Alzheimer disease. An anti-inflammatory effect has also been suggested. The heterodimer nuclear receptor Liver-X-Receptor(alpha)/Retinoid-X-Receptor (LXR(alpha)/RXR) is considered to be a transcription factor for apo E. The aim of this study was to determine whether lipopolysaccharide (LPS) (principal component of the outer membrane Gram-negative bacteria) has an effect on apo E secretion by intestinal mucosa cells, using the Caco-2 cell line. Differentiated Caco-2 cells grown on filter inserts were incubated apically with LPS and/or 25-hydroxycholesterol (25-OH chol) and 9 cis retinoic acid (9cRA), ligands of LXR and RXR, respectively. The apical and basolateral media were separately collected. Apo E was detected by specific antibodies after protein separation by Two-dimensional nondenaturing gradient gel electrophoresis and apo E secreted in the cell culture media was measured by enzyme linked immunosorbent assay (ELISA). Apo E mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). LXR(alpha) and RXR mass was analyzed by Western Blot. We demonstrate here that CaCo-2 cells secrete apo E, by either apical or basolateral sides, associated with a high-density like lipoprotein, with a stoke's diameter comprised between 7.10 and 8.16 nm. We show that only apical secretion is decreased by LPS in a dose and time dependent manner. This is associated with a decrease in apo E gene expression contrasting with an increase of Il-8, a chemokine factor. Moreover, we demonstrate that only basolateral apo E secretion by CaCo-2 is significantly increased by 25-OH chol and 9cRA while apical secretion remains unchanged. LPS does not decrease the 25-OH chol and 9cRA mediated apo E secretion in basolateral compartment, while apical secretion is diminished under these circumstances. Our results provide evidence for the polarized secretion of apo E by intestinal epithelium. They also demonstrate that apo E secretion by CaCo-2 cell line is decreased by LPS through an LXR(alpha)/RXR independent signaling pathway.
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PMID:Effect of LPS on basal and induced apo E secretion by 25-OH chol and 9cRA in differentiated CaCo-2. 1499 70


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