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)

Investigation into the etiology of atherosclerosis has identified cigarette smoking as a major risk factor. Although it has been established that cellular adhesion molecule expression on endothelial cells is stimulated by nicotine, the mechanism by which this occurs is not clear. The aim of this study was to determine the effect of nicotine on the expression of the adhesion molecules, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells and to determine the involvement of important known intermediaries, protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), and the transcription factors NF-kappaB and AP-1. Human umbilical vein endothelial cells (HUVEC) were exposed to 10-8 M nicotine for up to 24 h. Expression of ICAM-1 and VCAM-1 and phosphorylation of p38 were examined by immunoblot. Electrophoretic mobility shift assay was performed to determine NF-kappaB and AP-1 activation. We observed that nicotine increased the expression of ICAM-1 and VCAM-1 with a peak at 6 h. p38 MAPK was activated after 5 min exposure to 10-8 mol/L nicotine and returned to baseline levels by 30 min. Exposure of HUVEC to nicotine resulted in a 4.1-fold increase of PKC activity at 5 min, which subsequently returned to control levels by 15 min. Nicotine (10-8 mol/L) also increased NF-kappaB and AP-1 activity. Inhibitors of p38 MAPK, PKC, and NF-kappaB suppressed nicotine-stimulated expression of ICAM-1 and VCAM-1. Our results indicate that nicotine enhances the expression of ICAM-1 and VCAM-1 on the endothelial cell surface via a second messenger pathway which involves PKC and p38 MAPK-mediated activation of NF-kappaB and AP-1, resulting in increased expression of these cellular adhesion molecules.
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PMID:Nicotine enhances human vascular endothelial cell expression of ICAM-1 and VCAM-1 via protein kinase C, p38 mitogen-activated protein kinase, NF-kappaB, and AP-1. 1684 81

Cardiovascular disease is the main cause of death and disability in the Western society. Lipoproteins are important in the development of cardiovascular disease since they change the properties of different cells involved in atherosclerosis and thrombosis. The interaction of platelets with lipoproteins has been under intense investigation. Particularly the initiation of platelet signaling pathways by low density lipoprotein (LDL) has been studied thoroughly, since platelets of hypercholesterolemic patients, whose plasma contains elevated LDL levels due to absent or defective LDL receptors, show hyperaggregability in vitro and enhanced activity in vivo. These observations suggest that LDL enhances platelet responsiveness. Several signaling pathways induced by LDL have been revealed in vitro, such as signaling via p38 mitogen-activated protein kinase and p125 focal adhesion kinase. High density lipoprotein (HDL) consists of two subtypes, HDL(2) and HDL(3), which have opposing effects on platelet activation. This review provides a summary of the activation of signaling pathways after platelet-LDL and platelet-HDL interaction, with special emphasis on their role in the development of thrombosis and atherosclerosis.
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PMID:Platelet activation by low density lipoprotein and high density lipoprotein. 1687 76

Both statins and peroxisome proliferator-activated receptor (PPAR)gamma ligands have been reported to protect against the progression of atherosclerosis. In the present study, we investigated the effects of statins on PPARgamma activation in macrophages. Statins increased PPARgamma activity, which was inhibited by mevalonate, farnesylpyrophosphate, or geranylgeranylpyrophosphate. Furthermore, a farnesyl transferase inhibitor and a geranylgeranyl transferase inhibitor mimicked the effects of statins. Statins inhibited the membrane translocations of Ras, RhoA, Rac, and Cdc42, and overexpression of dominant-negative mutants of RhoA (DN-RhoA) and Cdc42 (DN-Cdc42), but not of Ras or Rac, increased PPARgamma activity. Statins induced extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) activation. However, DN-RhoA and DN-Cdc42 activated p38 MAPK, but not ERK1/2. ERK1/2- or p38 MAPK-specific inhibitors abrogated statin-induced PPARgamma activation. Statins induced cyclooxygenase (COX)-2 expression and increased intracellular 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) levels through ERK1/2- and p38 MAPK-dependent pathways, and inhibitors or small interfering RNA of COX-2 inhibited statin-induced PPARgamma activation. Statins also activate PPARalpha via COX-2-dependent increases in 15d-PGJ(2) levels. We further demonstrated that statins inhibited lipopolysaccharide-induced tumor necrosis factor alpha or monocyte chemoattractant protein-1 mRNA expression, and these effects by statins were abrogated by the PPARgamma antagonist T0070907 or by small interfering RNA of PPARgamma or PPARalpha. Statins also induced ATP-binding cassette protein A1 or CD36 mRNA expression, and these effects were suppressed by small interfering RNAs of PPARgamma or PPARalpha. In conclusion, statins induce COX-2-dependent increase in 15d-PGJ(2) level through a RhoA- and Cdc42-dependent p38 MAPK pathway and a RhoA- and Cdc42-independent ERK1/2 pathway, thereby activating PPARgamma. Statins also activate PPARalpha via COX-2-dependent pathway. These effects of statins may explain their antiatherogenic actions.
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PMID:Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. 1752 75

Adiponectin is the most abundantly secreted adipocyte-derived peptide hormone, possessing an array of antidiabetogenic and cardiovascular protective effects. Acting through 2 distinct membrane receptors, adiponectin receptors 1 and 2 (which utilize 5'-adenosine monophosphate-activated protein kinase phosphorylation, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha as key cell signaling elements), adiponectin increases hepatic and skeletal muscle sensitivity to insulin, enhances fatty acid oxidation, suppresses monocyte-endothelial interaction, supports endothelial cell growth, lowers blood pressure, and moderates adipose tissue growth. The secretion of adiponectin can be suppressed by adipose factors, which are turned on once fat cell mass increases, such as cytokines, adipose renin-angiotensin system, and increased oxidative stress. Inhibition of adiponectin secretion results in the loss of an array of mechanisms, which under normal conditions of fat cell homeostasis provide protection from insulin resistance, diabetes, and atherosclerosis.
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PMID:Hypoadiponectinemia as a marker of adipocyte dysfunction -- Part I: the biology of adiponectin. 1778 81

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

Soluble intercellular adhesion molecule-1 (sICAM-1), a circulating form of ICAM-1, has been known to be involved in the development of vascular diseases that are associated with vascular smooth muscle cell migration, such as hypertension and atherosclerosis. Here we investigated the contributions of sICAM-1 in promoting vascular migration in rat aortic smooth muscle cells (RASMCs). sICAM-1 increased RASMC migration, and this response was stronger in spontaneously hypertensive rats (SHRs) than in Wistar Kyoto (WKY) rats. The CD11a, CD11b, and CD18 subunits of ICAM-1 receptors were expressed in both SHRs and WKY rats; however, the expression levels of CD18 and CD11b were greater in SHRs than in WKY rats. The neutralization of the receptor subunits with anti-CD11a and -CD18 antibodies abolished the sICAM-1-increased migration. The treatment of inhibitors of spleen tyrosine kinase (Syk) and p38 mitogen-activated protein kinase suppressed the sICAM-1-stimulated migration of RASMCs. sICAM-1 also increased the sprout formation in aortic rings on Matrigel, and this response was inhibited by treatment with these inhibitors. The results suggest that sICAM-1 play crucial roles in vascular cell function through Syk pathways, and that the altered responses of sICAM-1 in RASMCs from SHRs may be mediated by the increased expression of the CD18 receptor.
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PMID:Contribution of soluble intercellular adhesion molecule-1 to the migration of vascular smooth muscle cells. 1799 63

Atherosclerosis is a complex vascular inflammatory disease. Oxidized low-density lipoprotein (ox-LDL) is directly associated with chronic vascular inflammation. In this study, we hypothesized that nonselective cyclooxygenase inhibitor aspirin might affect the ox-LDL-induced inflammatory responses on human endothelial cells. To test this assumption, cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1) expression, IkappaB and p38 mitogen-activated protein kinase (MAPK) phosphorylation were determined in endothelial cells exposed to ox-LDL in the presence of aspirin. The results showed that aspirin significantly suppressed COX-2 and ICAM-1 expression induced by ox-LDL and also inhibited IkappaB phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, aspirin reduced the level of p38 MAPK phosphorylation. Our findings suggest that aspirin can decrease inflammatory responses induced by ox-LDL, and the mechanism might be associated with NF-kappaB activation pathway and inhibition of p38 MAPK phosphorylation.
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PMID:Protective effects of aspirin against oxidized LDL-induced inflammatory protein expression in human endothelial cells. 1820 66

C-reactive protein (CRP) is present in the atherosclerotic plaques and appears to promote atherogenesis. Intraplaque CRP colocalizes with oxidized low density lipoprotein (OxLDL) and macrophages in human atherosclerotic lesions. Matrix metalloproteinase-9 (MMP-9) has been implicated in plaque rupture. CRP promotes OxLDL uptake and MMP induction in vitro; however, these have not been investigated in vivo. We examined the effect of CRP on OxLDL uptake and MMP-9 production in vivo in Wistar rats. CRP significantly increased OxLDL uptake in the peritoneal and sterile pouch macrophages compared with human serum albumin (huSA). CRP also significantly increased intracellular cholesteryl ester accumulation compared with huSA. The increased uptake of OxLDL by CRP was inhibited by pretreatment with antibodies to CD32, CD64, CD36, and fucoidin, suggesting uptake by both scavenger receptors and Fc-gamma receptors. Furthermore, CRP treatment increased MMP-9 activity in macrophages compared with huSA, which was abrogated by inhibitors to p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), and nuclear factor (NF)-kappaB but not Jun N-terminal kinase (JNK) before human CRP treatment. Because OxLDL uptake by macrophages contributes to foam cell formation and MMP release contributes to plaque instability, this study provides novel in vivo evidence for the role of CRP in atherosclerosis.
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PMID:Human C-reactive protein promotes oxidized low density lipoprotein uptake and matrix metalloproteinase-9 release in Wistar rats. 1824 17

Monocyte chemoattractant protein (MCP)-1 plays a key role in atherosclerosis and inflammation associated with visceral adiposity by inducing mononuclear cell migration. Evidence shows that mouse peritoneal macrophages (MPM) express a 12-lipoxygenase (12/15-LO) that has been clearly linked to accelerated atherosclerosis in mouse models and increased monocyte endothelial interactions in both rodent and human cells. However, the role of 12/15-LO products in regulating MCP-1 expression in macrophages has not been clarified. In this study, we tested the role of 12/15-LO products using MPM and the mouse macrophage cell line, J774A.1 cells. We found that 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] increased MCP-1 mRNA and protein expression in J774A.1 cells and MPM. In contrast, 12(R)-HETE, a lipid not derived from 12/15-LO, did not affect MCP-1 expression. 15(S)-HETE also increased MCP-1 mRNA expression, but the effect was less compared with 12(S)-HETE. MCP-1 mRNA expression was upregulated in a macrophage cell line stably overexpressing 12/15-LO (Plox-86 cells) and in MPM isolated from a 12/15-LO transgenic mouse. In addition, the expression of MCP-1 was downregulated in MPM isolated from 12/15-LO knockout mice. 12(S)-HETE-induced MCP-1 mRNA expression was attenuated by specific inhibitors of protein kinase C (PKC) and p38 mitogen-activated protein kinase (p38). 12(S)-HETE also directly activated NADPH oxidase activity. Two NADPH oxidase inhibitors, apocynin and diphenyleneiodonium chloride, blocked 12(S)-HETE-induced MCP-1 mRNA. Apocynin attenuated 12(S)-HETE-induced MCP-1 protein secretion. These data show that 12(S)-HETE increases MCP-1 expression by inducing PKC, p38, and NADPH oxidase activity. These results suggest a potentially important mechanism linking 12/15-LO activation to MCP-1 expression that induces inflammatory cell infiltration.
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PMID:Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages. 1829 57

Endothelial cells (ECs) play an important role in hypoxia-induced vascular disorders. We investigated the acute hypoxia effect on endothelial expression of activating transcription factor 3 (ATF3), a stress-inducible transcription factor playing significant roles in cellular responses to stress. Bovine aortic ECs were subjected to acute hypoxia (1% O(2), pO(2)=8 mmHg) and ATF3 expression was examined. ECs exposed to hypoxia transiently induced ATF3 expression. A transient increase in the activation of c-Jun-NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in ECs was observed; however, only ECs pretreated with a specific inhibitor to JNK suppressed the hypoxia-induced ATF3 expression. ECs exposed to acute hypoxia transiently increased endothelial nitric oxide (eNOS) activity. Pre-treating ECs with a specific inhibitor to eNOS (l-NAME) or PI3-kinase significantly inhibited the hypoxia-induced JNK activation and ATF3 expression. ATF3 induction has been shown to inhibit matrix metalloproteinase-2 (MMP-2) expression. Consistently, ECs exposed to hypoxia attenuated the MMP-2 expression. This hypoxia-attenuated MMP-2 expression can be rescued by pre-treating ECs with an inhibitor of eNOS. These results suggest that the ATF3 induction by acute hypoxia is mediated by nitric oxide and the JNK pathway in ECs. Our findings provide a molecular basis for the mechanism in which ECs respond to acute hypoxia.
Atherosclerosis 2008 Dec
PMID:Acute hypoxia to endothelial cells induces activating transcription factor 3 (ATF3) expression that is mediated via nitric oxide. 1837 12


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