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)

Polychlorinated biphenyls (PCBs) may contribute to the pathology of atherosclerosis by activating inflammatory responses in vascular endothelial cells. Endothelial nitric oxide synthase (eNOS) is colocalized with caveolae and is a critical regulator of vascular homeostasis. PCBs may be proatherogenic by causing dysfunctional eNOS signaling. The objective of this study was to investigate the role of caveolin-1 in PCB-induced endothelial dysfunction with a focus on mechanisms associated with eNOS signaling. Cells derived from an immortalized human vascular endothelial cell line were treated with PCB77 to study nitrotyrosine formation through eNOS signaling. Phosphorylation studies of eNOS, caveolin-1, and kinases, such as Src, phosphatidylinositol 3-kinase (PI3K), and Akt, were conducted in cells containing either functional or small-interfering RNA-silenced caveolin-1 protein. We also investigated caveolin-1-regulated mechanisms associated with PCB-induced markers of peroxynitrite formation and DNA binding of NF-kappaB. Cellular exposure to PCB77 increased eNOS phosphorylation and nitric oxide production, as well as peroxynitrite levels. A subsequent PCB-induced increase in NF-kappaB DNA binding may have implications in oxidative stress-mediated inflammatory mechanisms. The activation of eNOS by PCB77 treatment was blocked by inhibitors of the Src/PI3K/Akt pathway. PCB77 also increased phosphorylation of caveolin-1, indicating caveolae-dependent endocytosis. Caveolin-1 silencing abolished both the PCB-stimulated Akt and eNOS phosphorylation, suggesting a regulatory role of caveolae in PCB-induced eNOS signaling. These findings suggest that PCB77 induces eNOS phosphorylation in endothelial cells through a Src/PI3K/Akt-dependent mechanism, events regulated by functional caveolin-1. Our data provide evidence that caveolae may play a critical role in regulating vascular endothelial cell activation and toxicity induced by persistent environmental pollutants such as coplanar PCBs.
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PMID:The role of caveolin-1 in PCB77-induced eNOS phosphorylation in human-derived endothelial cells. 1793 68

Intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play critical roles in mediating monocyte adhesion to the vascular endothelium and monocyte migration into the subendothelial regions of the vessels. Inasmuch as cardiotrophin-1 (CT-1), an IL-6-type cytokine, was expressed in human atherosclerotic plaque, we examined whether CT-1 induces monocyte adhesion and migration by stimulating gene and protein expressions of ICAM-1 and MCP-1 in human aortic endothelial cells (HAECs). Immunocytochemistry revealed that CT-1 increased intensity of ICAM-1 and MCP-1 immunoreactivity in HAECs. Adhesion assay and chemotaxis assay revealed that CT-1 increased human monocytic THP-1 cell adhesion to HAECs and promoted chemotaxis in THP-1 cells, which were attenuated by anti-ICAM-1 and anti-MCP-1 antibody, respectively. Western blot analysis showed that CT-1 increased phosphorylation of ERK1/2 MAP kinase, p38 MAP kinase, and Akt and that their inhibitors, PD-98059, SB-203580, and LY-294002, respectively, inhibited phosphorylation. RNase protection assay and ELISA demonstrated that CT-1 increased gene and protein expressions of ICAM-1 and MCP-1. EMSA revealed that CT-1 enhanced NF-kappaB DNA-binding activity. CT-1-mediated upregulation of ICAM-1 and MCP-1 was suppressed by PD-98059, SB-203580, LY-294002, and parthenolide. The present study demonstrates that CT-1 promotes monocyte adhesion and migration by stimulating ICAM-1 and MCP-1 through mechanisms that involve ERK1/2 MAP kinase, p38 MAP kinase, phosphatidylinositol 3-kinase, and NF-kappaB pathways and suggests that CT-1 plays an important role in the pathophysiology of vascular inflammation and atherosclerosis.
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PMID:Cardiotrophin-1 stimulates intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in human aortic endothelial cells. 1805 23

Recruitment of leukocytes to inflammatory sites is crucial in the pathogenesis of chronic inflammatory diseases. The aim of this study was to investigate if activation of CB2 cannabinoid receptors would modulate the chemotactic response of human monocytes. Human monocytes treated with the CB2 agonist JWH-015 for 12-18 h showed significantly reduced migration to chemokines CCL2 and CCL3, associated with reduced mRNA and surface expression of their receptors CCR2 and CCR1. The induction of ICAM-1 in response to IFN-gamma was inhibited by JWH-015. Moreover, JWH-015 cross-desensitized human monocytes for migration in response to CCL2 and CCL3 by its own chemoattractant properties. The CB2-selective antagonist SR-144528, but not the CB1 antagonist SR-147778, reversed JWH-015-induced actions, whereas the CB2 agonist JWH-133 mimicked the effects of JWH-015. The investigation of underlying pathways revealed the involvement of phosphatidylinositol 3-kinase/Akt and ERK1/2 but not p38 MAPK. In conclusion, selective activation of CB2 receptors modulates chemotaxis of human monocytes, which might have crucial effects in chronic inflammatory disorders such as atherosclerosis or rheumatoid arthritis.
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PMID:CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. 1820 43

Type 2 diabetes is associated with a two to fourfold increased risk of both coronary heart disease and stroke. Dysfunction of endothelial cells (EC) is known to promote abnormal vascular growth such as that in atherosclerosis and arteriosclerosis and has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes mellitus, and hyperglycemia is an independent risk factor for the development of cardiovascular disease. We and others have previously demonstrated that high D-glucose induced apoptosis through activation of the bax-caspase proteases pathway in human EC and the potential contribution of hepatocyte growth factor, as an anti-apoptotic factor, to the pathogenesis of endothelial dysfunction. The anti-apoptotic action of HGF was due to bcl-2-upregulation and the phosphatidylinositol 3-kinase pathway, which is involved in Akt activation. Although it has been known for years that cardiovascular tissues can release a large amount ROS, including superoxide, hydrogen peroxide, and nitric oxide, the role of oxidative stress in atherogenesis has received increasing attention in recent years. Recent work strongly suggests that NADPH oxidase is a major source of superoxide in cardiovascular cells, and oxidative stress can be involved in the process of endothelial dysfunction. NADPH oxidase can be activated in hyperglycemia through the protein kinase C pathway. From the viewpoint of these molecular mechanisms, HMG-CoA reductase inhibitors (statins) might inhibit the high glucose-induced NADPH oxidase activation through inhibition of Rac activity and finally prevent the increase in ROS production in diabetes. A recent clinical trial suggested that statins prevent several vascular events in patients with type 2 diabetes without a high concentration of LDL-cholesterol. These pleiotropic effects of statins can be expected to improve endothelial dysfunction through nitric oxide production and/or an anti-oxidant effect in diabetic patients.
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PMID:Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. 1822 May 82

Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme which catalyzes group heme into carbon monoxide, iron and bilirubin. In the recent years, HO-1 expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress. In this regard, induction of this enzyme has shown beneficial effects in several pathologic conditions, such as inflammatory processes, atherosclerosis, carcinogenesis, ischemia-reperfusion systems or degenerative diseases. Complex intracellular signalling cascades mediate the expression of HO-1 in response to external stimuli, Transcription factors, as nuclear factor E2-related factor-2, activator protein-1, and nuclear factor-kappa B, and some of their upstream kinases, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, or protein kinases A, C are responsible of the HO-1 gene expression. The purpose of this article is to review the increasing number of natural and synthetic molecules reported to induce HO-1 as additive mechanism responsible for their therapeutic effects; experimental and pathological conditions as well as possible signalling mechanism involved in HO-1 expression by this compounds are described. Controlled upregulation of this enzyme, or its catalytic activity, has shown antioxidant, anti-proliferative, anti-apoptotic and anti-inflammatory properties. For this reason, pharmacologic modulation of HO-1 system may represent an effective and cooperative strategy to intervene in several pathologic conditions.
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PMID:Inducers of heme oxygenase-1. 1828 74

In the present study, we assessed that cilostazol stimulates differentiation of 3T3-L1 fibroblasts into adipocytes, and to improve insulin sensitivity in conjunction with PPARgamma transcriptional activity. Upon treatment of COS-7 cells and human umbilical vein endothelial cells (HUVECs) with cilostazol (10 and 30 microM), endogenous PPARgamma transcriptional activity was significantly elevated in both cells as did rosiglitazone (10 microM), and these effects were suppressed by 5 microM GW9662, an antagonist of PPARgamma activity. Cilostazol-induced 3T3-L1 fibroblast differentiation into adipocytes in concert with increases in expression of PPARgamma responsive genes such as CCAAT enhancer binding protein alpha (C-EBPalpha), aP2, which were accompanied by increased adiponectin and decreased resistin expressions as did rosiglitazone. These variables were strongly suppressed by GW9662, indicative of a PPARgamma-mediated signaling. GLUT4 protein expression and glucose uptake were significantly elevated by cilostazol as was by rosiglitazone, which were also attenuated by GW9662, indicative of improvement of insulin sensitivity. Signaling pathways involved in the cilostazol-stimulated PPARgamma transcription activity in HUVECs included phosphatidylinositol 3-kinase (PI3-kinase)/AKT. Taken together, it is suggested that cilostazol increases differentiation of 3T3-L1 fibroblasts into adipocytes, and improves insulin sensitivity by stimulating PPARgamma transcription.
Atherosclerosis 2008 Dec
PMID:Cilostazol increases 3T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-gamma transcription. 1835 28

Human cytomegalovirus (HCMV) infection is associated with atherosclerosis, transplant vascular sclerosis, and coronary restenosis. A common theme in these vascular diseases is an increased rate of angiogenesis. Angiogenesis is a complex biological process mediated by endothelial cell (EC) proliferation, migration, and morphogenesis. Although angiogenesis is a normal process in the host, its dysregulation, after viral infection or injury to the vessel wall, is associated with plaque development in atherosclerotic patients. We now document that HCMV infection results in increased EC proliferation, motility, and capillary tube formation. The observed HCMV-induced angiogenic response depended on viral binding to and signaling through the beta(1) and beta(3) integrins and the epidermal growth factor receptor, via their ability to activate the phosphatidylinositol 3-kinase and the mitogen-activated protein kinase signaling pathways. Because a proangiogenic response drives the neovascularization observed in atherosclerotic disease, our findings identify a possible mechanism for how HCMV infection contributes to vascular disease.
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PMID:Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. 1837 53

The E-cadherin/beta-catenin/T-cell factor (Tcf) signaling pathway plays a crucial role in embryogenesis and carcinogenesis and has recently emerged in atherosclerosis. The aim of this work was to investigate whether this signaling pathway is involved in smooth muscle cell proliferation induced by oxidized low-density lipoprotein (LDL). In human aortic smooth muscle cells, mitogenic concentration of mildly oxidized LDL induced the activation of beta-catenin, as assessed by the dissociation of the beta-catenin/cadherin complex, and the concomitant rise of active beta-catenin in the cytosol. The oxidized LDL-induced rise of active beta-catenin required metalloproteinase activation, as well as epidermal growth factor receptor and Src signaling, as assessed by the use of pharmacological inhibitors and cells overexpressing a SrcK-inactive form. The concomitant phosphatidylinositol 3-kinase/Akt activation and glycogen synthase kinase 3-beta phosphorylation induced the inhibition of the proteasomal degradation of beta-catenin. Then active beta-catenin associated with Tcf4 and translocated into the nucleus. This enhanced the expression of the cell cycle activator cyclin D1. This crucial role of beta-catenin in the mitogenic effect of oxidized LDL was confirmed by silencing beta-catenin by specific small interfering RNA that blocked DNA synthesis. Immunohistochemistry staining of stable and disrupted plaques from carotid endarterectomy sections showed a correlation between active beta-catenin and Ki67, a proliferation marker, and a more intense staining in the smooth muscle cell layer surrounding the lipid core of disrupted plaques. In conclusion, the beta-catenin pathway is required for the mitogenic effect of oxidized LDL on human aortic smooth muscle cells. This study highlights the putative important role of the E-cadherin/beta-catenin/Tcf signaling pathway in atherosclerosis.
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PMID:E-cadherin/beta-catenin/T-cell factor pathway is involved in smooth muscle cell proliferation elicited by oxidized low-density lipoprotein. 1870 80

Oxidized LDL (OxLDL) is thought to play a role in the pathogenesis of early as well as advanced stages of atherosclerosis. One possible mechanism involves local upregulation of pro-inflammatory cytokines such as vascular endothelial growth factor (VEGF). This study was done to define the mechanism by which OxLDL increases secretion of VEGF in macrophages. The murine leukemia-derived RAW 264.7 macrophage cell line as well as mouse peritoneal macrophages and human monocyte-derived macrophages were used in these studies. Cells were exposed to native low-density lipoprotein (LDL), acetylated LDL, and LDL that had been modified by oxidation with copper or ferrous ions or by exposure to auto-oxidation products of arachidonic acid for 16h, and VEGF was then assayed in medium. Pharmacological inhibitors of phosphatidylinositol 3-kinase (PI3K) or PKCzeta blocked VEGF secretion by OxLDL. Inhibitors of other protein kinase C (PKC) subtypes had no effect, and neither did inhibitors of mitogen activated protein kinase kinase (MAPKK). We found that LDL with oxidative modification of either its lipid or protein component can induce VEGF expression. Higher degrees of oxidation of LDL conferred higher potency to induce VEGF. Macrophages from mice lacking both scavenger receptors A (SR-A) and CD36 were fully responsive to OxLDL with regard to VEGF secretion. These macrophages show an 85% reduction in OxLDL uptake compared to macrophages from wild-type mice. Macrophages from mice lacking LOX-1 were also fully responsive to oxLDL with regard to VEGF secretion. We conclude that VEGF upregulation is mediated through PI3K and PKCzeta, and does not involve the above three scavenger receptors or require uptake of oxidized LDL.
Atherosclerosis 2009 May
PMID:VEGF secretion by macrophages is stimulated by lipid and protein components of OxLDL via PI3-kinase and PKCzeta activation and is independent of OxLDL uptake. 1878 2

Angiotensin receptor-1 blockers (ARBs) have been used for the treatment of atherosclerosis. Tight junctions are very important in the regulation of cellular permeability which may have a profound role in atherosclerosis. The relationship between them is unresolved. The expression and distribution of zonula occludens-1 (ZO-1), the permeability of cultured endothelial cells, and the activity of phosphatidylinositol 3-kinase (PI3K) were all detected with various methods after cultured endothelial cells were exposed to valsartan and the special ARB telmisartan or combined with PI3K inhibitor wortmannin or the peroxisome proliferator-activated receptor gamma antagonist GW9662. We found that telmisartan but not valsartan downregulated ZO-1 mRNA and protein levels, disrupted the distribution of ZO-1 in cultured endothelial cells, and increased the permeability of endothelial cells in a dose-dependent manner. When the PI3K inhibitor wortmannin was used, the effect induced by telmisartan was at least partly reversed. The role of the PI3K signaling pathway was further confirmed in the PI3K activity assay. GW9662 significantly blocked telmisartan-induced ZO-1 changes. Our results suggest that telmisartan disrupts the continuous pericellular distribution of ZO-1, downregulates the expression of ZO-1 in endothelial cells, and increases the permeability of endothelial cells at least partly through PI3K and the peroxisome proliferator-activated receptor gamma-dependent pathway.
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PMID:Telmisartan increases the permeability of endothelial cells through zonula occludens-1. 1925 88


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