Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

Nuclear factor kappa B (NF-kappa B) activation has been observed in human atherosclerotic plaques and is enhanced in unstable coronary plaques, but whether such activation has a protective or pathophysiological role remains to be determined. We addressed this question by developing a short-term culture system of cells isolated from human atherosclerotic tissue, allowing efficient gene transfer to directly investigate signaling pathways in human atherosclerosis. We found that NF-kappa B is activated in these cells and that this activity involves p65, p50, and c-Rel but not p52 or RelB. This NF-kappa B activation can be blocked by overexpression of I kappa B alpha or dominant-negative I kappa B kinase (IKK)-2 but not dominant-negative IKK-1 or NF-kappa B-inducing kinase, resulting in selective inhibition of inflammatory cytokines (tumor necrosis factor alpha, IL-6, and IL-8), tissue factor, and matrix metalloproteinases without affecting the antiinflammatory cytokine IL-10 or tissue inhibitor of matrix metalloproteinases. Our results demonstrate that the canonical pathway of NF-kappa B activation that involves p65, p50, c-Rel, and IKK-2 is activated in human atherosclerosis and results in selective up-regulation of major proinflammatory and prothrombotic mediators of the disease.
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PMID:Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. 1506 95

The leukocyte- type 12/15-Lipoxygenase (12/15-LO) enzyme and its oxidized lipid products play important roles in vascular smooth muscle cell (VSMC) growth, migration, and matrix responses associated with hypertension, atherosclerosis, and restenosis. However, much less is known about their inflammatory effects. In this study, we showed that the 12/15-LO product of linoleic acid, 13-hydroperoxyocta decadienoic acid (13-HPODE) can transcriptionally upregulate the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) in VSMC. We also observed reduced activation of the transcription factor, NF-kappa B and reduced expression of MCP-1/JE mRNA in VSMC from 12/15-LO knock-out mice relative to WT. To confirm the role of NF-kappa B in 13-HPODE-induced MCP-1 expression and to selectively block the induction of such inflammatory genes in VSMC, we designed novel molecular approaches to knockdown NF-kappa B with short interfering RNAs (siRNAs). We designed siRNAs to human NF-kappa B p65 transcriptionally active subunit by using a rapid PCR-based approach that generates sense and antisense siRNA separated by a hairpin loop downstream of the U6 promoter. siRNA PCR products targeting seven different sites on p65 cDNA could induce upto 92% reduction in HA-p65 protein levels. A six-fold decrease in NF-kappa B-dependent luciferase activity was also seen. Transfection of human VSMC with these siRNA PCR products resulted in 70% reduction in p65 protein levels. We cloned the PCR products into a pCR3.1 vector and these p65 siRNA expressing plasmids very effectively blocked 13-HPODE-induced expression of both MCP-1 and TNF-alpha genes. These results show for the first time that 13-HPODE can induce MCP-1 in the vasculature via activation of NF-kappa B.
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PMID:Regulation of monocyte chemoattractant protein-1 by the oxidized lipid, 13-hydroperoxyoctadecadienoic acid, in vascular smooth muscle cells via nuclear factor-kappa B (NF-kappa B). 1508 18

Pentraxin-3 (PTX3), an acute-phase protein that belongs to the family of the PTXs, is found elevated in septic shock and increased in patients with acute myocardial infarction. As tissue factor (TF) plays a key role in thrombosis and inflammation associated with atherosclerosis and as we have recently reported that PTX3 increases TF synthesis in endothelial cells, we tested whether PTX3 could modulate TF expression in monocytes. Monocytes from peripheral blood of healthy donors were incubated with highly purified PTX3 with or without lipopolysaccharide (LPS). Cells were then disrupted, and procoagulant activity was assessed by a one-stage clotting time. PTX3 enhanced TF activity and antigen from LPS-stimulated monocytes in a dose-dependent way. The effect was specific, as other PTXs, such as C-reactive protein and serum amyloid P component, were ineffective. Moreover, the increase in activity was specific for LPS, as in the presence of other TF-inducing agents such as interleukin-1beta and tumor necrosis factor alpha, PTX3 was not effective. The increase in TF activity requires mRNA synthesis, as assessed by polymerase chain reaction. The mechanism by which PTX3 modulates TF synthesis resides in an enhanced IkappaB, alpha phosphorylation and degradation and increased migration of the transacting factor c-Rel/p65 into the nucleus, as determined by Western blot and electro-mobility shift assay. These results show that PTX3 is an enhancer of the expression of TF by mononuclear cells. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. PTX3 increases TF expression, thus potentially playing a role in thrombogenesis and wound healing.
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PMID:The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation. 1522 67

The adipocyte exerts an important role in energy homeostasis, both as depot for energy-rich triglycerides and as a source for metabolic hormones. Adipocytes also contribute to inflammation and the innate immune response. Although it can be physiologically beneficial to combine these two functions in a single cell type under some circumstances, the proinflammatory signals emanating from adipocytes in the obese state can have local and systemic effects that promote atherosclerosis and insulin resistance. The transcriptional machinery in the adipocyte that mediates these pro-inflammatory responses has remained poorly characterized to date. In particular, no information is currently available on the NF-kappaB family of transcription factors. Here, we show that adipogenesis is associated with changes in amount and subunit composition of the NF-kappaB complexes. NF-kappaB subunits p65 (RelA), p68 (RelB), and IkappaB are upregulated during fat cell differentiation. Correspondingly, basal NF-kappaB nuclear gel shift and luciferase reporter assays are induced in parallel during differentiation. Surprisingly, endotoxin sensitivity of the classical NF-kappaB pathway is substantially delayed and attenuated despite increased overall inflammatory response in the mature adipocyte, as judged by induction of IL-6 and TNF-alpha. As a reflection of the constitutively elevated NF-kappaB activity in the mature adipocyte, adipocytes (but not preadipocytes) exert a strong inflammatory stimulus on macrophages in vitro, suggesting a cross talk between adipocytes and interstitial macrophages in adipose tissue in vivo. These effects are mediated by a secretory product of adipocytes that is unlikely to be IL-6 or TNF-alpha.
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PMID:Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity. 1525 65

Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.
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PMID:Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. 1532 87

Inflammation is a key event in the development of atherosclerosis. Nuclear factor-kappaB (NF-kappaB) is important in the inflammatory response regulation. The effector peptide of the renin angiotensin system Angiotensin II (Ang II) activates NF-kappaB and upregulates some related proinflammatory genes. Our aim was to investigate whether other angiotensin-related peptides, as the N-terminal degradation peptide Ang IV, could regulate proinflammatory factors (activation of NF-kappaB and related genes) in cultured vascular smooth muscle cells (VSMCs). In these cells, Ang IV increased NF-kappaB DNA binding activity, caused nuclear translocation of p50/p65 subunits, cytosolic IkappaB degradation and induced NF-kappaB-dependent gene transcription. Ang II activates NF-kappaB via AT1 and AT2 receptors, but AT1 or AT2 antagonists did not inhibit NF-kappaB activation caused by Ang IV. In VSMC from AT1a receptor knockout mice, Ang IV also activated NF-kappaB pathway. In those cells, the AT4 antagonist divalinal diminished dose-dependently Ang IV-induced NF-kappaB activation and prevented IkappaB degradation, but had no effect on the Ang II response, indicating that Ang IV activates the NF-kappaB pathway via AT4 receptors. Ang IV also increased the expression of proinflammatory factors under NF-kappaB control, such as MCP-1, IL-6, TNF-alpha, ICAM-1, and PAI-1, which were blocked by the AT4 antagonist. Our results reveal that Ang IV, via AT4 receptors, activates NF-kappaB pathway and increases proinflammatory genes. These data indicate that Ang IV possesses proinflammatory properties, suggesting that this Ang degradation peptide could participate in the pathogenesis of cardiovascular diseases.
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PMID:Angiotensin IV activates the nuclear transcription factor-kappaB and related proinflammatory genes in vascular smooth muscle cells. 1583 14

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. In vascular diseases, such as atherosclerosis, inflammation plays an important role in the pathogenesis of the disease. We examined the role of LPL in modulating tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs). LPL significantly suppressed TNF-alpha-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase. In contrast, LPL synergistically enhanced IFN-gamma-induced gene expression in HAECs. To elucidate the molecular mechanisms of LPL action, we investigated the role of transcription factors nuclear factor kappa B (NF-kappaB) and signal transducer and activator of transcription factor 1 (Stat1). The anti-inflammatory response of LPL in suppressing TNF-alpha-induced gene expression was a result of its inhibition of NF-kappaB activity by the abrogation of IkappaB-alpha degradation and phosphorylation of the p65 subunit. Although LPL alone had no effect on Stat1 activation, LPL enhanced IFN-gamma-induced phosphorylation of Stat1 on tyrosine 701 and serine 727, as well as Stat1-mediated transactivation. The synergistic effect of LPL on IFN-gamma-induced Stat1 activation was mediated by enhanced activation of the tyrosine kinase JAK2 and was abrogated by LY294002, a specific inhibitor of the phosphatidylinositol 3'-kinase pathway. Our studies indicate that LPL has differential effects on several inflammatory pathways known to be important in atherosclerosis.
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PMID:Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells. 1599 21

Chronic inhibition of nitric oxide (NO) synthesis by administration of high dose of N(G)-nitro-L-arginine methylester (L-NAME) induces vascular inflammation and subsequent atherosclerosis. We aimed to investigate whether the methanol extract of Sorbus commixta cortex (MSC) is able to prevent inflammatory process in a rat model of L-NAME-induced atherosclerosis. Chronic treatment with low or high doses of MSC prevented the L-NAME-induced increase in monocyte chemoattractant protein-1 (MCP-1) and nuclear factor-kappaB (NF-kappaB) p65 expressions as well as adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in aorta. In addition, increased endothelin-1 (ET-1) and angiotensin converting enzyme (ACE) expressions and decreased endothelial cell NO synthase (ecNOS) expression in aorta from L-NAME treated group was reversed by treatment with MSC. From the histological examination, aortic segment from the L-NAME-treated rats revealed a thickening of intima and media, which was ameliorated by treatment with MSC. In conclusion, our results indicate that MSC can prevent atherosclerosis by inhibiting vascular over-expressions of vasoactive materials, pro-inflammatory transcription factor, and adhesion molecules and by augmenting ecNOS in chronic L-NAME-treated rat model.
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PMID:Effect of methanol extract of Sorbus cortex in a rat model of L-NAME-induced atherosclerosis. 1599 6

Recent studies have shown that C-reactive protein (CRP) is not just a predictor of cardiovascular events but also acts directly as a proinflammatory stimulus in vascular cells. In this report, we studied the molecular mechanisms underlying vascular cellular adhesion molecule-1 (VCAM-1) induction by CRP. CRP-induced VCAM-1 mRNA expression and this induction was inhibited by protein kinase C (PKC) inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitor, and tyrosine kinase inhibitors. In addition, parthenolide, a nuclear factor kappaB (NF-kappaB) inhibitor, abolished VCAM-1 induction. Moreover, CRP increased VCAM-1 promoter activity, indicating that CRP induces VCAM-1 mRNA expression at the transcriptional level. Mutation of NF-kappaB-binding sites resulted in a loss of induction. Finally, an electrophoretic mobility shift assay confirmed binding of the p65 subunit of NF-kappaB to kappaB-binding sites. Taken together, our findings suggest that VCAM-1 induction by CRP is mediated by PKC, p38MAPK, tyrosine kinase and the NF-kappaB-dependent signaling pathways in vascular endothelial cells.
Atherosclerosis 2006 Mar
PMID:C-reactive protein induces VCAM-1 gene expression through NF-kappaB activation in vascular endothelial cells. 1600 75


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