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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dioxin is known to cause many toxic effects that vary greatly in different tissues, ages, genders, and species. In this review, an attempt has been made to sort out major signaling pathways involved in the expression of the toxicities of dioxin. The major strategy adopted in analyzing its major signaling pathways is to view the toxic actions of dioxin as the result of the Ah receptor-mediated expression of a major cellular emergency stress response signal. Evidence pointing to the similarities between the symptoms of poisoning by dioxin and those produced by chronic administration of typical stressors, particularly lipopolysaccharides (LPS), bacterial endotoxins, has been assembled and analyzed. The common symptoms are wasting syndrome, atherosclerosis, fatty liver, and thymic atrophy. On the other hand, oxidative stress caused by cytochrome P450 induction is one of the typical stresses of dioxin poisoning, but not LPS poisoning. One of the major means through which dioxin triggers stress responses via "stress-activated kinase pathways" is stimulation of the cellular production of cytokines/autocrines, particularly growth factors. In the case of hepatocytes for instance, transforming growth factor-alpha plays a pivotal role in the dioxin-induced activation of the epidermal growth factor receptor and the extracellular signal-related kinase pathway, which acts as a signal to suppress apoptosis induced by cellular stress. These observations as well as additional experimental data support the idea that one of the major functions of the Ah receptor could be the elicitation of cellular stress response reactions. Another key point in understanding the toxic action of dioxin is that, unlike other cases of stressors, dioxin signaling becomes chronically sustained because of its extreme persistence in the human body, its half-life of 7-10 years, and its selective accumulation in fatty target tissues.
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PMID:On the significance of the role of cellular stress response reactions in the toxic actions of dioxin. 1290 18

Enhanced production of reactive oxygen species (ROS) such as H(2)O(2) and a failure in ROS removal by scavenging systems are hallmarks of several cardiovascular diseases such as atherosclerosis and hypertension. ROS act as second messengers that play a prominent role in intracellular signaling and cellular function. In vascular smooth muscle cells (VSMCs), a vascular pathogen, angiotensin II, appears to initiate growth-promoting signal transduction through ROS-sensitive tyrosine kinases. However, the precise mechanisms by which tyrosine kinases are activated by ROS remain unclear. In this review, the current knowledge that suggests how certain tyrosine kinases are activated by ROS, along with their functional significance in VSMCs, will be discussed. Recent findings suggest that transactivation of the epidermal growth factor receptor by ROS requires metalloprotease-dependent heparin-binding epidermal growth factor-like growth factor production, whereas other ROS-sensitive tyrosine kinases such as PYK2, JAK2, and platelet-derived growth factor receptor require activation of protein kinase C-delta. Each of these ROS-sensitive kinases could mediate specific signaling critical for pathophysiological responses. Detailed analysis of the mechanism of cross-talk and the downstream function of these various tyrosine kinases will yield new therapeutic interventions for cardiovascular disease.
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PMID:Activation of tyrosine kinases by reactive oxygen species in vascular smooth muscle cells: significance and involvement of EGF receptor transactivation by angiotensin II. 1458 50

AngII (angiotensin II) and its G-protein-coupled AT(1) receptor play critical roles in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. It is widely believed that AngII promotes these diseases by inducing vascular remodelling that involves hypertrophy, hyperplasia and migration of VSMCs (vascular smooth muscle cells). We have shown that transactivation of an ErbB family receptor, EGFR (epidermal growth factor receptor; ErbB1), is essential for VSMC hypertrophy and migration induced by AngII. However, the precise signal transduction mechanism by which AngII transactivates EGFR/ErbB1 and whether other ErbBs are also required for AngII function remains unclear. Recent studies suggest an involvement of a metalloprotease-dependent ErbB family ligand production in the transactivation. Here, we will discuss the roles and mechanisms of AngII/AT(1) receptor in promoting ErbB receptors transactivation in VSMCs. Further elucidation of this ErbB activation machinery not only will give us a better understanding of the critical molecular mechanism underlying vascular remodelling stimulated by AngII, but will also contribute to development of novel treatment strategies for cardiovascular diseases.
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PMID:Metalloprotease-dependent ErbB ligand shedding in mediating EGFR transactivation and vascular remodelling. 1464 Oct 25

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

Reactive oxygen species are profoundly important for many physiologic functions and are also pivotal to numerous disease processes, particularly those involving inflammation. Much evidence has accrued demonstrating that aldosterone acts locally in many cells aside from those in the cortical collecting duct. Peripheral blood monocytes and vascular smooth muscle cells are both influenced by aldosterone to produce reactive oxygen species. This production contributes to nuclear factor kappaB (NF-kappaB) activation and the genes regulated by this transcription factor. Aldosterone thereby plays an important role in atherosclerosis and hypertension-induced vascular injury. Aldosterone interacts with angiotensin (Ang) II-induced signaling. Both aldosterone and Ang II initiate ERK1/2 and JNK signaling; the effects of the two compounds is additive and involves the epidermal growth factor receptor. Recent data suggest that reactive oxygen species, might contribute to aldosterone production in nonadrenal tissues. A novel oxidized derivative of linoleic acid is a prime candidate in this regard. Oxidative stress may impair mineralocorticoid receptor function by inhibiting aldosterone binding. The latter finding has particularly important implications for elderly persons who exhibit increased oxidative stress and who are at risk for diminished aldosterone function in the distal nephron and subsequent hyperkalemia.
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PMID:The mineralocorticoid receptor and oxidative stress. 1594 91

The epidermal growth factor receptor is a member of type-I growth factor receptor family with tyrosine kinase activity that is activated following the binding of multiple cognate ligands. Several members of the EGF family of ligands are expressed by cells involved in atherogenesis. EGF receptor mediated processes have been well characterised within epithelial, smooth muscle and tumour cell lines in vitro, and the EGF receptor has been identified immunocytochemically on intimal smooth muscle cells within atherosclerotic plaques. There is also limited evidence for the expression of the EGF receptor family on leukocytes, although their function has yet to be clarified. In this review, we will discuss the biological functions of this receptor and its ligands and their potential to modulate the function of cells involved in the atherosclerotic process.
Atherosclerosis 2006 May
PMID:The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis. 1607 71

Endothelial membrane-bound thrombomodulin is a high affinity receptor for thrombin to inhibit coagulation. We previously demonstrated that the thrombin-thrombomodulin complex restrains cell proliferation mediated through protease-activated receptor (PAR)-1. We have now tested the hypothesis that thrombomodulin transduces a signal to activate the endothelial nitric-oxide synthase (NOS3) and to modulate G protein-coupled receptor signaling. Cultured human umbilical vein endothelial cells were stimulated with thrombin or a mutant of thrombin that binds to thrombomodulin and has no catalytic activity on PAR-1. Thrombin and its mutant dose dependently activated NO release at cell surface. Pretreatment with anti-thrombomodulin antibody suppressed NO response to the mutant and to low thrombin concentration and reduced by half response to high concentration. Thrombin receptor-activating peptide that only activates PAR-1 and high thrombin concentration induced marked biphasic Ca2+ signals with rapid phosphorylation of PLC(beta3) and NOS3 at both serine 1177 and threonine 495. The mutant thrombin evoked a Ca2+ spark and progressive phosphorylation of Src family kinases at tyrosine 416 and NOS3 only at threonine 495. It activated rapid phosphatidylinositol-3 kinase-dependent NO synthesis and phosphorylation of epidermal growth factor receptor and calmodulin kinase II. Complete epidermal growth factor receptor inhibition only partly reduced the activation of phospholipase Cgamma1 and NOS3. Prestimulation of thrombomodulin did not affect NO release but reduced Ca2+ responses to thrombin and histamine, suggesting cross-talks between thrombomodulin and G protein-coupled receptors. This is the first demonstration of an outside-in signal mediated by the cell surface thrombomodulin receptor to activate NOS3 through tyrosine kinase-dependent pathway. This signaling may contribute to thrombomodulin function in thrombosis, inflammation, and atherosclerosis.
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PMID:Endothelial thrombomodulin induces Ca2+ signals and nitric oxide synthesis through epidermal growth factor receptor kinase and calmodulin kinase II. 1612 27

Low-density lipoprotein (LDL) is an important carrier of plasma cholesterol and triglycerides whose concentration is regulated by the liver parenchymal cells. Abnormal LDL regulation is thought to cause atherosclerosis, while viral binding to LDL has been suggested to facilitate hepatitis C infection. Primary hepatocytes quickly lose the ability to clear LDL during in vitro culture. Here we show that the coculture of hepatocytes with liver sinusoidal endothelial cells (LSEC) significantly increases the ability of hepatocytes to uptake LDL in vitro. LDL uptake does not increase when hepatocytes are cocultured with other cell types such as fibroblasts or umbilical vein endothelial cells. We find that LSECs induce the hepatic expression of the LDL receptor and the epidermal growth factor receptor. In addition, while hepatocytes in single culture did not take up hepatitis C virus (HCV)-like particles, the hepatocytes cocultured with LSECs showed a high level of HCV-like particle uptake. We suggest that coculture with LSECs induces the emergence of a sinusoidal surface in primary hepatocytes conducive to the uptake of HCV-like particles. In conclusion, our findings describe a novel model of polarized hepatocytes in vitro that can be used for the study of LDL metabolism and hepatitis C infection.
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PMID:Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes. 1644 Mar 37

Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT(1)), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.
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PMID:Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature. 1647 78

Cell-surface receptor tyrosine kinases play pivotal roles in development, tissue repair, and normal cellular homeostasis. Aberrant expression or signaling patterns of these kinases has also been linked to the progression of a diversity of diseases, including cancer, atherosclerosis, asthma, and fibrosis. Two major families of receptor tyrosine kinases, the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) families, have received a great deal of attention as potential therapeutic targets for pulmonary diseases, as these receptors have been shown to play key roles in chronic tissue remodeling in asthma, bronchitis, and pulmonary fibrosis. The EGFR system on epithelial cells and underlying mesenchymal cells (fibroblasts, myofibroblasts, and smooth muscle cells) drives numerous phenotypic changes during the progression of these pulmonary diseases, including epithelial cell mucous cell metaplasia and mesenchymal cell hyperplasia, differentiation, and extracellular matrix production. The PDGFR system, located primarily on mesenchymal cells, transduces signals for cell survival, growth and chemotaxis. The variety of EGFR and PDGFR ligands produced by the airway epithelium or adjacent mesenchymal cells allows for intimate epithelial-mesenchymal cell communication. A full understanding of the complex mechanisms involving these receptors and ligands should lead to therapeutic strategies for the treatment of a wide range of fibroproliferative lung diseases.
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PMID:EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases. 1690 Jun 64


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