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)

The transcriptional regulatory protein nuclear factor kappa B (NF-kappa B) participates in the control of gene expression of many modulators of inflammatory and immune responses, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). The heightened expression of these adhesion molecules has been reported to play a critical role in atherosclerosis, inflammation, ischemic vascular disorders, diabetes, and cancer metastasis. In the present study, we investigated the effect of pycnogenol, an antioxidant phytochemical, on the activation of NF-kappa B and the induction of VCAM-1 and ICAM-1 in tumor necrosis factor (TNF)-alpha-treated human umbilical vein endothelial cells (HUVECs). Gel-shift analysis of HUVEC demonstrated that pretreatment with pycnogenol exhibited a concentration-dependent suppression of TNF-alpha-induced activation of NF-kappa B. Induction of VCAM-1 and ICAM-1 surface expression by TNF-alpha was dose-dependently reduced by pycnogenol. TNF-alpha significantly increased the release of superoxide anion and hydrogen peroxide from HUVECs. Pycnogenol dose-dependently inhibited their release. The ability of pycnogenol to inhibit NF-kappa B activation and VCAM-1 and ICAM-1 expression suggests that this phytochemical may play an important role in halting or preventing the atherogenic process.
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PMID:Pycnogenol inhibits tumor necrosis factor-alpha-induced nuclear factor kappa B activation and adhesion molecule expression in human vascular endothelial cells. 1089 47

Aging is associated with increased inflammatory activity. Increased plasma levels of tumour necrosis factor (TNF)-alpha were found in centenarians aged 100 years and in individuals aged 80-81 years when compared to a young control group. Plasma levels of TNF-alpha were linearly correlated to plasma levels of interleukin (IL)-6, TNF-receptors and C-reactive protein. High levels of TNF-alpha were directly related to dementia and to a low blood pressure ankle-arm index, indicating generalized atherosclerosis. In hospitalized patients with Streptococcus pneumonia infection, aging was associated with prolonged inflammatory activity. Similar results were found using an in vivo endotoxin challenge model in old versus young humans. Strenuous exercise induces increased levels in a number of proinflammatory and anti-inflammatory cytokines, naturally occurring cytokine inhibitors and chemokines. Thus, increased plasma levels of TNF-alpha, IL-1, IL-6, IL-1 receptor antagonist (IL-Ira), TNF-receptors (TNF-R), IL-10, IL-8 and macrophage inflammatory protein (MIP)-1 are found after strenuous exercise. The cytokine response to strenuous exercise has similarities to the cytokine response to trauma and sepsis. Therefore, in future studies, exercise is suggested as an ethically applicable model to use in studies on mechanisms underlying the age-associated altered cytokine response.
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PMID:Cytokines in aging and exercise. 1089 17

Ageing is associated with increased inflammatory activity in the blood. The purpose of this study was to investigate if age-related increased plasma levels of TNF-alpha were associated with atherosclerosis in a cohort of 130 humans aged 81 years. The elderly cohort had increased circulating levels of TNF-alpha, C-reactive protein (CRP), total cholesterol (TC), low-density lipoproteins (LDL) and a low high-density lipoprotein (HDL)/TC ratio compared with a young control group (n = 44). The elderly cohort was divided by tertiles into three subgroups with low, intermediate, and high levels of TNF-alpha, respectively. In the group with high TNF-alpha concentrations a significantly larger proportion had clinical diagnoses of atherosclerosis. Furthermore, weak correlations were found between TNF-alpha on one hand and blood concentrations of triglycerides, leucocytes, CRP and a low HDL/TC ratio on the other which are known as risk factors of atherogenesis and thromboembolic complications. No correlations were found between TNF-alpha, TC, LDL, or the body mass index. In conclusion, the present study shows that in a cohort of 81-year-old humans, high levels of TNF-alpha in the blood were associated with a high prevalence of atherosclerosis.
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PMID:Ageing, tumour necrosis factor-alpha (TNF-alpha) and atherosclerosis. 1093 Nov 39

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARgamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARgamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.
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PMID:Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. 1097 14

Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis. Selected dietary lipids (eg, fatty acids) may be atherogenic by activating endothelial cells and by potentiating an inflammatory response. Due to their prooxidant property, unsaturated fatty acids may play a critical role in endothelial cell activation and injury. To test this hypothesis, porcine endothelial cells were exposed to 18-carbon fatty acids differing in the degree of unsaturation, ie, 90 micromol/L stearic (18:0), oleic (18:1n-9), linoleic (18:2n-6), or linolenic acid (18:3n-3) for 6 to 24 hours and/or tumor necrosis factor alpha ([TNF-alpha] 500 U/L) for up to 3 hours. Compared with control cultures, treatment with 18:0 and 18:2 decreased glutathione levels, suggesting an increase in cellular oxidative stress. Both 18:2 and 18:0 activated the transcription factor nuclear factor kappaB (NF-kappaB) the most and 18:1 the least. This NF-kappaB-dependent transcription was confirmed in endothelial cells by luciferase reporter gene assay. The fatty acid-mediated activation of NF-kappaB was blocked by preenrichment of the cultures with 25 micromol/L vitamin E. All fatty acids except 18:1 and 18:3 increased transendothelial albumin transfer, and 18:2 caused the most marked disruption of endothelial integrity. Preenrichment of endothelial cells with 18:2 followed by exposure to TNF-alpha resulted in a 100% increase in interleukin-6 (IL-6) production compared with TNF-alpha exposure alone. In contrast, cellular preenrichment with 18:0, 18:1, or 18:3 had no effect on TNF-alpha-mediated production of IL-6. Cellular release of radiolabeled arachidonic acid (20:4) was markedly increased only by cell exposure to 18:2 and 18:3, and the release of 20:4 appeared to be mainly from the phosphatidylethanolamine fraction. These data suggest that oleic acid does not activate endothelial cells. Furthermore, linoleic acid and other omega-6 fatty acids appear to be the most proinflammatory and possibly atherogenic fatty acids.
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PMID:Fatty acid-mediated activation of vascular endothelial cells. 1095 18

Hydroxymethylglutaryl CoA (HMG CoA) reductase inhibitors, or statins, have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. Atherosclerotic plaque lesions can be chronically inflamed and vulnerable to rupture or stable and less rupture-prone. Human smooth muscle cells (SMC) are critically important in maintaining the stability of atherosclerotic plaques. This stability may be greatly influenced by pro-inflammatory mediators such as IFN-gamma, TNF-alpha, and Il-1beta and Fas ligand (FasL) that are present in human atheroma. The purpose of the present study was to examine the effect of the statins on apoptosis of SMC. We have found that SMC are normally resistant to Fas or cytokine-induced apoptosis, but can be sensitized to these agents with pharmacological concentrations of some statins. Simvastatin and lovastatin strongly sensitized the cells to apoptotic agents while atorvastatin was less effective. In contrast to the lipophilic statins, the hydrophilic statin pravastatin did not induce this sensitization of SMC to apoptosis. Treatment of SMC with either mevalonate, the product of the HMG-CoA reductase, or geranylgeranylpyrophosphate, a down stream intermediate, prevented lipophilic statin-induced sensitization to apoptosis. These results suggest that prenylation of one or more proteins is critically involved in regulating the sensitivity of SMC to apoptotic stimuli. Our data support the emerging evidence that through this pathway the various statins may have effects which are beyond a simple lowering of the levels of circulating cholesterol.
Atherosclerosis 2000 Sep
PMID:Inhibitors of HMG-CoA reductase sensitize human smooth muscle cells to Fas-ligand and cytokine-induced cell death. 1099 58

Despite the improvements in dialysis technology, the cardiovascular mortality rate is still unacceptably high among dialysis patients. It is obvious that traditional risk factors, such as hypertension, chronic heart failure (CHF), dyslipidemia and diabetes mellitus, may account for a large part of the increased cardiovascular mortality rate in these patients. However, based on recent research it could be speculated that other, non-traditional risk factors might also contribute to the high cardiovascular mortality rate in dialysis patients. Chronic inflammation, as evidenced by increased levels of pro-inflammatory cytokines and C-reactive protein (CRP), is a common feature in dialysis patients and is associated with an increased cardiovascular morbidity and mortality. Indeed, elevated levels of pro-inflammatory cytokines (such as TNF-alpha, IL-1 and IL-6) may cause malnutrition and progressive atherosclerotic cardiovascular disease by several pathogenetic mechanisms, which will be discussed in this review. Based on the strong associations observed between malnutrition, inflammation and atherosclerosis in patients with chronic renal failure (CRF) we have proposed that these features constitute a specific syndrome (MIA), which carries a high mortality rate. As elevated levels of pro-inflammatory cytokines may play a central part in the vicious circle of malnutrition, inflammation and atherosclerosis, further research is needed to investigate whether or not different anti-cytokine treatment strategies may improve survival in dialysis patients.
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PMID:Inflammatory and atherosclerotic interactions in the depleted uremic patient. 1111 78

Cellular adhesion molecules play a pivotal role in the pathogenesis of atherosclerosis by mediating the adherence of blood leukocytes. Since hyperhomocysteinemia appears to be an independent risk factor for the development of atherosclerosis, in this study we investigated the effect of homocysteine on basal and TNF-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) on human umbilical-vein endothelial cells. Incubation of endothelial cells with homocysteine resulted in dose-dependent reduction in TNF-alpha-induced (5 ng/ml) expression of VCAM-1, E-selectin, and ICAM-1 (the latter less pronounced). This effect was found to be specific since other thiol compounds-cysteine and glutathione-did not mimic homocysteine activity. Homocysteine attenuated TNF-alpha-stimulated U-937 adhesion to the endothelial monolayer and reduced TNF-alpha-induced activation of the transcription factor NF-kappaB, indicating that NF-kappaB inhibition may play a role in inhibiting expression of adhesion molecules in endothelial cells.
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PMID:Homocysteine inhibits TNF-alpha-induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappaB dependent pathway. 1116 39

In addition to established factors such as hyperlipidemia, smoking and hypertension, inflammation and infection have recently been implicated as major risk factors for atherosclerotic disease. Proatherogenic effects induced by infection may be related to both systemic inflammation and to direct effects on the vascular wall. We report here that a high fat diet combined with a protozoal infection with known tropism to the heart induced early atherosclerosis and intimal inflammatory infiltrates (CD4+, CD8+ cells and macrophages) in aortas of all (n = 7) CBA/J mice investigated. These mice are normally quite resistant to atherosclerotic development and in the control group (n = 7) receiving only a fatty diet, only one mouse presented a lesion. This lesion was completely devoid of infiltrating CD8+ cells. Parasite-infected mice receiving a normal diet exhibited vasculitis, but no signs of atherosclerosis and control mice receiving normal diet, as expected, exhibited neither signs of vasculitis nor atherosclerosis. Secretion of IL-6, TNF-alpha, and IFN-gamma were demonstrated in all atherosclerotic lesions and IL-6 appeared to be the dominant cytokine, both in the lesions themselves as well as in the intimal-medial junction. There were no traces of parasites present in the artery wall, indicating that atherosclerosis was induced via an indirect route. We conclude that a high fat diet in conjunction with infection and systemic (or localized) inflammation may have a strong proatherogenic effect. Finally, we suggest that CBA/J mice infected with T. cruzi parasites and given a fatty diet could serve as a useful experimental model in the continued analysis of factors contributing to the induction of atherosclerosis.
Atherosclerosis 2000 Dec
PMID:Induction of early atherosclerosis in CBA/J mice by combination of Trypanosoma cruzi infection and a high cholesterol diet. 1116 16

The association of atherosclerosis with the most common risk factors including elevation of low density lipoprotein (LDL) levels, diabetes, hypertension and cigarette smoking, led to the hypothesis of "response to injury" to explain how the lesions develop. According to this hypothesis, one of the earliest events in atherogenesis is the accumulation of LDL in the arterial wall where they undergo oxidation. These LDL impair endothelial function, and thus, all the antiatherogenic properties of the endothelium. In addition, macrophages and smooth muscle cells take up these LDL, through different receptors, and become foam cells. The accumulation of foam cells in the arterial wall contributes to lesion development. Therefore, lesion development involves the activation of endothelial cells, as well as smooth muscle cells and monocytes/macrophages. In this activation different growth factors (PDGF, EGF, etc.), cytokines (IL-1b, TNFa, etc.) and the modified LDL themselves, play an important role. Through several signal transduction pathways these molecules activate transcription factors, such as the nuclear factor kappa B (NF-kB) or protooncogenes such as c-fos, c-myc, that regulate the expression of genes involved in the inflammatory/proliferative response of the lesions.
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PMID:[Cellular and molecular biology of atherosclerotic lesions]. 1118 11


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