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

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, while laminar flow and high shear stress are atheroprotective. Well characterized atheroprotective mechanisms include inhibition of thrombosis (increased tissue-type plasminogen activator and decreased plasminogen activator inhibitor-1), inhibition of endothelial cell apoptosis, limitation of permeability (uptake of low-density lipoprotein), prevention of white blood cell binding and transmigration (no expression of adhesion molecules such as intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1] and no release of monocyte chemotactic protein-1) and increased bioavailability of nitric oxide (because of increased expression of endothelial nitric oxide synthase and manganese superoxide dismutase). Our lab has investigated flow-mediated inhibition of inflammatory cytokine action. In particular, we have shown that flow prevents tumor necrosis factor-alpha (TNF-alpha) mediated signal transduction. TNF regulates inflammatory gene expression (e.g., ICAM-1 and VCAM-1) in endothelial cells, in part, by stimulating mitogen activated protein (MAP) kinases that phosphorylate transcription factors. We hypothesized that fluid shear stress inhibits TNF inflammatory effects on endothelial cells by inhibiting TNF mediated activation of the c-Jun N-terminal kinase. To test this hypothesis, we determined the effects of steady laminar flow on TNF-stimulated activity of c-Jun N-terminal kinase. The results show that flow inhibits c-Jun N-terminal kinase activation through multiple mechanisms, including stimulation of counter-regulatory MAP kinases (extracellular signal regulated kinases [ERK]1/2 and ERK5) and inhibition of apoptosis signal-regulated kinase. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms. These multiple mechanisms offer attractive targets for new drug therapies aimed at limiting atherosclerosis development and progression. (c) 2002 Prous Science. All rights reserved.
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PMID:Atheroprotective Mechanisms Activated by Fluid Shear Stress in Endothelial Cells. 1267 55

Atherosclerosis preferentially occurs in areas of turbulent blood flow and low fluid shear stress, whereas laminar blood flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent findings suggest a steady laminar blood flow decreases EC apoptosis and inhibits TNF-mediated EC activation. EC apoptosis or activation is suggested to be involved in plaque erosion, which may lead to platelet aggregation. TNF-alpha regulates gene expression in ECs, in part, by stimulating mitogen-activated protein (MAP) kinases, which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAP kinases in ECs. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm(2)) on TNF-alpha-stimulated activity of three MAP kinases in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. TNF-alpha activated ERK1/2, JNK, and p38 maximally at 15 min in HUVEC. Pre-exposing HUVEC for 10 min to flow inhibited TNF-alpha activation of JNK, but showed no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, a specific ERK1/2 inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Transfection studies with dominant-negative constructs of the protein kinase MEK5 suggested an important role for big mitogen-activated protein kinase 1 (BMK1) in flow-mediated regulation of EC activation by TNF-alpha. Understanding the mechanisms by which steady laminar flow regulates JNK activation by cytokines may provide insight into the atheroprotective mechanisms induced by laminar blood flow.
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PMID:Stress and vascular responses: atheroprotective effect of laminar fluid shear stress in endothelial cells: possible role of mitogen-activated protein kinases. 1268 37

Angiotensin-II (AII), the dominant effector of the renin-angiotensin system, is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis. Upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin in endothelial cells by inflammatory cytokines through nuclear factor kappa B (NFkappaB) activation is implicated in formation and progression of atherosclerotic plaque. Here we show that AII induces NFkappaB-dependent transcription in primary endothelial cell lines, leading to the upregulation of ICAM-1 and VCAM-1 expression. NFkappaB activation by AII is mediated by the NFkappaB-inducing kinase (NIK), a common mediator of NFkappaB activation by inflammatory cytokines, such as TNF-alpha. However, NFkappaB stimulation by AII differs from that of TNF-alpha since a TNF-receptor associated factor 2 (TRAF-2) dominant negative mutant does not prevent AII-mediated NFkappaB activation. In analogy with TNF-alpha-dependent activation of NFkappaB, treatment with either the anti-oxidant N-acetyl cysteine (NAC) or the cyclooxygenase (COX) inhibitor acetyl salicylic acid (aspirin), but not indometacin, prevents the induction of NFkappaB-dependent transcription by AII. Thus, production of reactive oxygen species, aspirin (asp)-sensitive enzymes of the arachidonate metabolism, and NIK are common transducers of AII- and TNF-dependent pathways to NFkappaB. AII also activates the inflammatory p38 kinase in endothelial cells, an effect inhibited by exposure to either NAC or asp. Pharmacological interference of the p38 pathway, with the inhibitor SB 202190, prevented AII-mediated activation of the NFkappaB target V-CAM, without affecting degradation of IkappaBalpha. These results support a pro-inflammatory effect of the vasoactive peptide AII in endothelial cells, through at least two pathways-NFkappaB and p38-both of which are sensitive to asp and antioxidants.
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PMID:Endothelial activation by angiotensin II through NFkappaB and p38 pathways: Involvement of NFkappaB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin. 1270 49

Type 2 diabetic mellitus (type 2 DM) comprises more than 95% of all Taiwanese patients with DM. Tumor necrosis factor-alpha (TNF-alpha) expression is linked with insulin resistance, and is under strong genetic control. The correlation between TNF promoter genotypes and type 2 DM is still controversial, because discrepancies among different studies exist. Ethnic differences play certain roles in these conflicting results, because the distribution of TNF promoter polymorphisms is different among study subjects with different racial origins. Therefore, we examined the relationship between the incidence of type 2 diabetes in Taiwanese and two polymorphisms of the TNF-alpha promoter region (positions -238 and -308) as well as the correlation between these polymorphisms and the patients' biochemical manifestations. Genomic DNA was extracted from peripheral blood cells of 261 Taiwanese patients with type 2 DM and 189 non-diabetic control study subjects, and their TNF promoter G-238A and G-308A polymorphisms were analyzed by PCR-RFLP analysis. No significant association between TNF-alpha G-238A and G-308A polymorphisms with type 2 diabetic incidence was observed. However, associations between TNF-alpha G-238A and low-density lipoprotein-cholesterol and between G-308A promoter polymorphism and high-fasting plasma glucose levels, using multiple linear regression analysis with adjustment for the subjects' age, sex, body mass index and diabetic status, were found. Our results suggested that though TNF-alpha G-238A and G-308A polymorphisms were not involved in the pathogenesis of type 2 DM, type 2 diabetic patients carrying TNFA-A or TNF-308*2 genotype might be more susceptible to diabetic complications such as atherosclerosis.
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PMID:TNF-alpha polymorphisms and type 2 diabetes mellitus in Taiwanese patients. 1275 58

Obstructive sleep apnoea (OSA) is a very prevalent disorder particularly amongst middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness'. In 1997, we first reported that the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor-alpha (TNF alpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNF alpha plasma levels and the body mass index (BMI). In subsequent studies, we showed that IL-6, TNF alpha, leptin and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnoea. The association of OSA with insulin resistance and diabetes type 2 has been confirmed since then in several epidemiological and clinical studies. Furthermore, our findings that women with polycystic ovary syndrome (PCOS, a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness support the pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnoea and sleepiness may be manifestations of a serious metabolic disorder, namely the Metabolic or Visceral Obesity Syndrome, include: obesity without sleep apnoea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity and age; and increased prevalence of sleep apnoea in postmenopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA. In conclusion, accumulating evidence provides support to our model of the bi-directional, feedforward, pernicious association between sleep apnoea, sleepiness, inflammation and insulin resistance, all promoting atherosclerosis and cardiovascular disease.
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PMID:Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. 1282 41

The observation that systemic inflammatory rheumatic diseases such as rheumatoid arthritis (RA) are associated with a significantly increased rate of cardiovascular disease, which often occurs at a younger age than in the normal population, is particularly important given the increasing interest in the role of inflammation in atherogenesis in the general population. This review examines the accumulating evidence for accelerated atherogenesis of RA and updates the hypothesis that vasculitis plays a major role in this. Endothelial dysfunction (ECD), widely regarded as initial lesion in atherogenesis, has been shown to occur commonly in primary vasculitis. This ECD is a diffuse event, demonstrable in more than one vascular bed. It is not simply due to scarring in the vessel wall, related to the focal inflammation of the underlying vasculitis, since it may be reversed by suppression of the immune inflammation. However, the mechanisms for this ECD differ from that of the primary vasculitis. Preliminary evidence suggests that inflammatory mediators such as CRP, TNF, or sphingolipids may be involved. The diffuse ECD of vasculitis may have important consequences for both the progression of the primary disease and for cardiovascular events. A model for the role of vasculitis-induced ECD in the accelerated atherogenesis of rheumatic diseases is presented. These concepts are discussed together with the messages they suggest for 'idiopathic' atherosclerosis in the general population.
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PMID:Accelerated atherogenesis in autoimmune rheumatic diseases. 1284 89

Oxidised low density lipoprotein (oxLDL) is one factor that may cause the immune reaction in the artery wall characteristic of atherosclerosis. OxLDL can promote immune activation as determined by enhanced secretion of IFN-gamma and TNF by immune competent cells. We previously demonstrated that Platelet-activating factor (PAF)-like lipids and/or lysophosphatidylcholine (LPC) in OxLDL contribute significantly to this immune activation, but these factors may also inhibit immune activation, at higher concentrations. We here demonstrate that IL-12 induces enhanced IFN-gamma secretion in peripheral blood mononuclear cells (PBMC), with no addition of a specific antigen, as determined by ELISPOT. Antibodies to IL-12 and to MHC class II inhibited both IL-12- and oxLDL-induced IFN-gamma secretion. OxLDL induced IL-12 production in PBMC. In the presence of IL-10, a T helper 2 cytokine, oxLDL induced a decreased IFN-gamma secretion, indicating that the local cytokine-milieu may determine the immunological properties of oxLDL. IL-10 could also be induced by OxLDL. Mononuclear leukocytes were prepared directly from human atherosclerotic plaques obtained at carotid operations. OxLDL had the capacity to induce IL-12, IL-10 and TNF from plaque cells using ELISPOT. Taken together, our data indicate that oxLDL can modulate immune reactivity in atherosclerosis by a nonspecific mechanism. OxLDL can be inhibitory, especially at higher concentrations. However, oxLDL can also promote immune activation by functioning as an adjuvant, potentiating and/or modulating immune-reactions via IL-12 and other cytokines including IL-10. This suggests that a specific T cell epitope in oxLDL is not necessary for oxLDL-induced T cell activation.
Atherosclerosis 2003 Jul
PMID:Oxidised LDL modulates immune-activation by an IL-12 dependent mechanism. 1286 Feb 53

The adipose tissue plays a fundamental role in maintaining the energy balance in mammals. During periods of high energy intake, the adipocytes store energy in the form of fat (triglycerides), which can be mobilized as free fatty acids during energy deprivation. Adipose tissue can no longer be considered only as a passive tissue that simply stores energy. Some recent discoveries have made it evident that this is a very active endocrine tissue that secretes important molecules related to different processes such as the immune response (TNF alpha) the regulation of food intake and expenditure of energy (leptin, Acrp30/adipoQ) and the vascular function (angiotensin and plasminogen activator inhibitor type 1). Alterations in the growth, development and function of the adipose tissue might therefore be involved in the development of different pathologies such as obesity, insulin resistance and type 2 diabetes, hypertension and atherosclerosis. A deeper understanding of the adipose tissue (morphology, development-adipogenesis, role in the metabolism and in the regulation of body weight, endocrine functions.) is needed for an adequate study of the underlying aspects in the development of obesity.
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PMID:[Adipose tissue: a storage and secretory organ]. 1286 Dec 68

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

Inflammatory cytokine synthesis by monocyte-macrophages in the developing plaque represents an important amplification point in atherosclerotic disease progression. Here we have investigated whether the state of monocyte-macrophage differentiation can influence TNF alpha synthesis in response to scavenged modified low-density lipoprotein (LDL). We show that LDL modified by nitration induces TNF alpha synthesis when added to undifferentiated human monocytes or a mouse cell line (RAW264.7) bearing an incompletely differentiated phenotype. However, significantly reduced levels of TNF alpha were released from in vitro differentiated human macrophages (P=0.006) or a mouse cell line (IC-21) bearing a well-differentiated macrophage phenotype (P<0.001). A possible scavenging insufficiency in macrophagic cell types was ruled out by lipoprotein-uptake studies and competency to synthesise TNF alpha was confirmed using lipopolysaccharide (LPS) as a stimulus. However, LPS-induced TNF alpha secretion in IC-21 cells was partially suppressed by pre-treatment with nitrated LDL (46%, P=0.0076), with no equivalent effect seen in RAW264.7 cells. Based on these data, we hypothesise that the state of differentiation of intimal monocyte-macrophages may play an important role in their inflammatory response to scavenged modified lipoproteins and that the fully differentiated macrophage end-point may be associated with a non-inflammatory and therefore, atheroprotective, phenotype.
Atherosclerosis 2003 Oct
PMID:The state of macrophage differentiation determines the TNF alpha response to nitrated lipoprotein uptake. 1461


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