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)

Flavonoids are a group of naturally-occurring phenolic compounds in the plant kingdom, and many flavonoids are found with vascular protective properties. Nevertheless how the protective response is exerted by flavonoids is not well characterized. In view of the nuclear factor-kappaB (NFkappaB) may play a central role in the initiation of atherosclerosis, prevention of the activation of NFkappaB represents an important role in protecting vascular injury. In this study, the effects of flavonoids on NFkappaB/inhibitor-kappaB (IkappaB) system in ECV304 cells activated with tumor necrosis factor-alpha (TNFalpha) were examined. We investigated the inhibitory action of six flavonoids on IkappaB kinase (IKK) activity, an enzyme recently found to phosphorylate critical serine residues of IkappaB for degradation. Of six flavonoids tested, myricetin was found to strongly inhibit IKK kinase activity, and prevent the degradation of IkappaBalpha and IkappaBbeta in activated endothelial cells. Furthermore, myricetin was also found to inhibit NFkappaB activity correlated with suppression of monocyte adhesion to ECV304 cells. Therefore we conclude that flavonoids may be of therapeutic value for vascular disease through down regulation of NFkappaB/IkappaB system.
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PMID:Suppression of TNFalpha-mediated NFkappaB activity by myricetin and other flavonoids through downregulating the activity of IKK in ECV304 cells. 1044 Sep 30

NF-kappaB is a pleiotropic transcription factor implicated in the regulation of diverse biological phenomena, including apoptosis, cell survival, cell growth, cell division, innate immunity, cellular differentiation, and the cellular responses to stress, hypoxia, stretch and ischemia. In the heart, NF-kappaB has been shown to be activated in atherosclerosis, myocarditis, in association with angina, during transplant rejection, after ischemia/reperfusion, in congestive heart failure, dilated cardiomyopathy, after ischemic and pharmacological preconditioning, heat shock, burn trauma, and in hypertrophy of isolated cardiomyocytes. Regulation of NF-kappaB is complicated; in addition to being activated by canonical cytokine-mediated pathways, NF-kappaB is activated by many of the signal transduction cascades associated with the development of cardiac hypertrophy and response to oxidative stress. Many of these signaling cascades activate NF-kappaB by activating the IkappaB kinase (IKK) complex a major component of the canonical pathway. These signaling interactions occur largely via signaling crosstalk involving the mitogen-activated protein kinase/extracellular signalregulated kinase kinases (MEKKs) that are components of mitogen activated protein kinase (MAPK) signaling pathways. Additionally, there are other signaling factors that act more directly to activate NF-kappaB via IkappaB or by direct phosphorylation of NF-kappaB subunits. Finally, there are combinatorial interactions at the level of the promoter between NF-kappaB, its coactivators, and other transcription factors, several of which are activated by MAPK and cytokine signaling pathways. Thus, in addition to being a major mediator of cytokine effects in the heart, NF-kappaB is positioned as a signaling integrator. As such, NF-kappaB functions as a key regulator of cardiac gene expression programs downstream of multiple signal transduction cascades in a variety of physiological and pathophysiological states. We show that genetic blockade of NF-kappaB reduces infarct size in the murine heart after ischemia/reperfusion (I/R), implicating NF-kappaB as a major determinant of cell death after I/R. These results support the concept that NF-kappaB may be an important therapeutic target for specific cardiovascular diseases.
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PMID:NF-kappaB as an integrator of diverse signaling pathways: the heart of myocardial signaling? 1455 89

Atherosclerosis is now generally accepted as a chronic inflammatory condition. The transcription factor NF-kappaB is a key regulator of inflammation, immune responses, cell survival, and cell proliferation. To investigate the role of NF-kappaB activation in macrophages during atherogenesis, we used LDL receptor-deficient mice with a macrophage-restricted deletion of IkappaB kinase 2 (IKK2), which is essential for NF-kappaB activation by proinflammatory signals. These mice showed increased atherosclerosis as quantified by lesion area measurements. In addition, the lesions were more advanced and showed more necrosis and increased cell number in early lesions. Southern blotting revealed that deletion of IKK2 was approximately 65% in macrophages, coinciding with a reduction of 50% in NF-kappaB activation, as compared with controls. In both groups, the expression of differentiation markers, uptake of bacteria, and endocytosis of modified LDL was similar. Upon stimulation with LPS, production of TNF was reduced by approximately 50% in IKK2-deleted macrophages. Interestingly, we also found a major reduction in the anti-inflammatory cytokine IL-10. Our data show that inhibition of the NF-kappaB pathway in macrophages leads to more severe atherosclerosis in mice, possibly by affecting the pro- and anti-inflammatory balance that controls the development of atherosclerosis.
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PMID:Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. 1456 2

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

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

Viral and bacterial pathogens have long been suspected to affect atherogenesis directly. However, mechanisms linking innate immunity to chronic inflammatory diseases such as atherosclerosis are still poorly defined. Here we show that infection of primary human aortic smooth muscle cells (HAOSMC) with human cytomegalovirus (HCMV) leads to activation of the novel IkappaB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), a major effector of the cellular innate immune response. We demonstrate that part of the HCMV inflammatory response is most likely mediated via this novel kinase because the canonical IKK complex was only poorly activated upon infection of HAOSMC. An increase in TBK1 phosphotransferase activity led to a strong activation of the interferon regulatory factor (IRF)-3 transcription factor as measured by its C-terminal phosphorylation, dimerization, and DNA binding activity. In addition to TBK1, HAOSMC also express another IKK-related kinase isoform, IKKepsilon, albeit at a lower level. Nevertheless, both isoforms were required for full activation of IRF-3 by HCMV. The transcripts of proatherosclerotic genes Ccl5 (encoding for the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted)) and Cxcl10 (encoding for the chemokine IP-10 (interferon-gamma-inducible protein 10)) were induced in an IRF-3-dependent manner after HCMV infection of smooth muscle cells. In addition, cytokine arrays analysis showed that RANTES and IP-10 were the predominant chemokines present in the supernatant of HCMV-infected HAOSMC. Activation of the TBK1/IRF-3 pathway was independent of epidermal growth factor receptor and pertussis toxin-sensitive G protein-coupled receptor activation. Our results thus add additional molecular clues to a possible role of HCMV as a modulator of atherogenesis through the induction of a proinflammatory response that is, in part, dependent of an IKK-related kinase pathway.
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PMID:Roles of an IkappaB kinase-related pathway in human cytomegalovirus-infected vascular smooth muscle cells: a molecular link in pathogen-induced proatherosclerotic conditions. 1561 5

Fatty acid-binding proteins are cytosolic fatty acid chaperones, and the adipocyte isoform, aP2, plays an important role in obesity and glucose metabolism. Recently, this protein has been detected in macrophages where it strongly contributes to the development of atherosclerosis. Here, we investigated the role of aP2 in macrophage biology and the molecular mechanisms underlying its actions. We demonstrate that aP2-deficient macrophages display defects in cholesterol accumulation and alterations in pro-inflammatory responsiveness. Deficiency of aP2 alters the lipid composition in macrophages and enhances peroxisome proliferator-activated receptor gamma activity, leading to elevated CD36 expression and enhanced uptake of modified low density lipoprotein. The increased peroxisome proliferator-activated receptor gamma activity in aP2-deficient macrophages is also accompanied by a significant stimulation of the liver X receptor alpha-ATP-binding cassette transporter A1-mediated cholesterol efflux pathway. In parallel, aP2-deficient macrophages display reduced IkappaB kinase and NF-kappaB activity, resulting in suppression of inflammatory function including reduced cyclooxygenase-2 and inducible nitric-oxide synthase expression and impaired production of inflammatory cytokines. Our results demonstrate that aP2 regulates two central molecular pathways to coordinate macrophage cholesterol trafficking and inflammatory activity.
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PMID:The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. 1568 32

Tilianin has been shown to down-regulate TNF-alpha induced expression of vascular cell adhesion molecules in endothelial cells. In this study, we examined the anti-atherogenic effects and molecular mechanism of tilianin in vitro and in vivo. Male low-density lipoprotein receptor null mice (Ldlr-/-) fed a high cholesterol diet showed significant increases in the size of atherosclerotic lesions, as well as increased plasma levels of total cholesterol, triglycerides, and the pro-inflammatory cytokines TNF-alpha and IL-1beta, when compared with Ldlr-/- mice fed a normal diet. Mice fed the high cholesterol diet supplemented with tilianin showed significantly reduced lesion sizes and reductions in cytokine levels, without significant changes in serum cholesterol levels. Primary cultured peritoneal macrophages from Ldlr-/- mice showed increased level of TNF-alpha andIL-1beta mRNA in response to treatment with lipopolysaccharide; these increases were inhibited by co-treatment with tilianin. Moreover, tilianin inhibited NF-kappaB activation, as determined by electrophoretic mobility shift and NF-kappaB promoter assays. Upstream of NF-kappaB activation, tilianin inhibited IkappaB kinase activation and the subsequent phosphorylation and degradation of IkappaBalpha protein. These results suggest that tilianin ameliorates atherosclerosis by inhibiting the production of the NF-kappaB-dependent pro-inflammatory cytokines, TNF-alpha and IL-1beta, via the inhibition of IkappaB kinase activity.
Atherosclerosis 2005 May
PMID:Inhibition of cytokine-induced IkappaB kinase activation as a mechanism contributing to the anti-atherogenic activity of tilianin in hyperlipidemic mice. 1582 72

Roxithromycin (RXM), a macrolide antibiotic, is used in clinical trials to address secondary prevention of coronary heart disease. However, the effects of RXM on human coronary artery smooth muscle cells (CASMC) proliferation remain unclear. Human CASMC were stimulated with growth medium containing 5% fetal bovine serum and growth factors. RXM at 1 or 10 microg/ml, which are relevant to the therapeutic plasma levels, significantly suppressed mitogen-induced CASMC proliferation, assessed by WST-1 assay and cell counting. Flow cytometry analysis demonstrated that RXM suppressed mitogen-induced G1 to S progression on cell cycle. Western blot showed that RXM inhibited phosphorylation of retinoblastoma gene products, reduced protein levels of cyclin D1 and A, and restored downregulation of cyclin-dependent kinase (CDK) inhibitor p27kip1. The activities of CDK4 and CDK2 were suppressed by RXM without affecting their protein levels. When transfected with both IkappaB kinase alpha and beta constructs as nuclear factor-kappa B (NF-kappaB) activator, CASMC entered S phase at 24 h, and RXM inhibited it. Electrophoretic mobility shift assay and immunostaining of NF-kappaB p65 demonstrated that RXM inhibited mitogen-induced NF-kappaB activation. These results indicate that RXM is an inhibitor of human CASMC proliferation through modulating cell cycle regulatory proteins and inhibiting NF-kappaB signaling pathway.
Atherosclerosis 2005 Sep
PMID:Roxithromycin is an inhibitor of human coronary artery smooth muscle cells proliferation: a potential ability to prevent coronary heart disease. 1611 78

An optimal level of NO has protective effects in atherosclerosis, whereas large amounts contribute to septic shock. To study how statins, the potent inhibitors of cholesterol synthesis, regulate NO in the vascular wall, we determined their effects on interleukin-1beta (IL-1beta)- and lipopolysaccharide (LPS)-induced NO production in aortic vascular smooth muscle cells (VSMCs). Compared with the large amounts of NO and inducible NO synthase (iNOS) protein expression induced by LPS, the responses of IL-1beta were modest. Various statins were found to inhibit LPS-induced iNOS expression and NO production, although they potentiated IL-1beta responses. In addition, fluvastatin increased IL-1beta-induced p65 nuclear translocation and nuclear factor kappaB (NF-kappaB) activity, although it inhibited those induced by LPS. To address the role of small G proteins in statin's actions, farnesyl transferase inhibitors [alpha-hydroxyfarne-sylphosphonic acid and (2S)-2-[[(2S)-2-[(2S,3S)-2-[(2R)-2-amino-3-mercaptopropyl]amino]-3-methylpentyl]oxy]-1-oxo-3-phenylpropyl]amino]-4-(methylsulfonyl)-butanoic acid 1-methylethyl ester (L-744382)], Rac inhibitor (NSC23766), and Rho-associated kinase (ROCK) inhibitor [N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide dihydrochloride (Y-27632)] were used. We found that Y-27632 potentiated IL-1beta-induced iNOS expression, p65 nuclear translocation, IkappaB kinase (IKK), and NF-kappaB activation, whereas it had minimal effects on LPS-induced responses. In contrast, farnesyl transferase inhibitors blocked iNOS protein expression induced by LPS and IL-1beta, whereas NSC23766 had no effect. Further studies showed that LPS down-regulated Rho and ROCK activity, whereas IL-1beta increased them, suggesting a negative role of Rho and ROCK signaling, which is regulated in contrary manners by IL-1beta and LPS, in IKK/NF-kappaB activation. Through abrogating this negative signaling, statins differentially regulate iNOS expression induced by LPS and IL-1beta in VSMCs. These differential actions of statins on iNOS gene regulation might provide an additional explanation for the pleiotropic beneficial effects of statins.
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PMID:The role of Rho-associated kinase in differential regulation by statins of interleukin-1beta- and lipopolysaccharide-mediated nuclear factor kappaB activation and inducible nitric-oxide synthase gene expression in vascular smooth muscle cells. 1631 11


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