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)

T lymphocytes localize within lesions of two diametrically opposed expressions of atherosclerosis: stenosis-producing plaques and ectasia-producing abdominal aortic aneurysm (AAA). T(H)1 immune responses appear to predominate in human stenotic lesions. However, little information exists regarding the nature of the T-cell infiltrate in AAAs. We demonstrate here that AAAs predominantly express T(H)2-associated cytokines and correspondingly lack mediators associated with the T(H)1 response as determined by Western blot and immunohistochemical analysis. In particular, aneurysmal tissue expressed interleukin (IL)-4, IL-5, and IL-10, cytokines not or only faintly detected in nondiseased tissue or stenotic atheroma. In contrast, AAAs contained low levels of the T(H)1 characteristic cytokines IL-2 and IL-15, which are amply expressed in stenotic lesions. Notably, stenotic lesions, but not AAAs, contained mature forms of the interferon-gamma-inducing cytokines IL-12 and IL-18 as well as the IL-18-processing enzyme caspase-1. Moreover, aneurysmal tissue lacked the receptor for interferon-gamma, although both types of lesions contained this T(H)1-promoting cytokine. These findings suggest that the functional repertoire of T cells differs in stenotic and aneurysmal lesions, and provide a novel framework for understanding the mechanisms of these diametrically opposite expressions of atherosclerosis.
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PMID:T(H)2 predominant immune responses prevail in human abdominal aortic aneurysm. 1216 75

Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E-deficient (apoE-/-) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE-/- mice crossed with CD1d-/- (CD1d-/-apoE-/-) mice exhibited a 25% decrease in lesion size compared with apoE-/- mice. Administration of alpha-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE-/- mice, whereas it did not affect lesion size in apoE-/-CD1d-/- mice. Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.
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PMID:CD1d-dependent activation of NKT cells aggravates atherosclerosis. 1474 94

Cytokines are important mediators of inflammatory and proliferative responses in disease states including atherosclerosis. Genetic variations in cytokine production could potentially influence the outcome of these responses. The aim of this study was to determine whether cytokine gene polymorphism might influence the development of atherosclerotic renal artery stenosis. Sixty-six patients with atherosclerotic renal artery stenosis and 100 normal healthy individuals were genotyped for interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-2 promoter region polymorphism. TNF-a, TNF-d, and IL-10 microsatellite polymorphisms were also analyzed. The frequency of the anti-inflammatory cytokine IL-10 promoter (-1082 A positive) GA and AA genotypes which are associated with low production were higher in the patient group when compared to the control group. The AA-TT-AA homozygous genotype combination of three single-nucleotide polymorphisms at -1082, -819, and -592 in the IL-10 gene was also observed at a higher frequency in the patient group compared to the controls. The frequency of TNF-alpha, IL-6, and IL-2 polymorphisms did not show any significant difference between the patient and control groups. To correlate IL-10 genotypes with differences in IL-10 protein expression, in vitro mRNA and protein levels were analyzed in lipopolysaccharide-stimulated peripheral blood mononuclear cells from 22 patients with renal artery stenosis and 33 controls. Individuals genotyped as A positive at position -1082 produced lower levels of IL-10 protein and had lower copy numbers of mRNA when compared to individuals genotyped as A negative in both patient and control groups. The increased frequency of the low producer IL-10 promoter, -1082 A-positive genotype in patients with renal artery stenosis, suggests that IL-10 may protect against the development of atherosclerotic renovascular disease.
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PMID:Renovascular disease is associated with low producer genotypes of the anti-inflammatory cytokine interleukin-10. 1510 79

Recent developments into antherothrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis. Thrombosis may lead to a complete occlusion or, in the case of mural thrombus or intraplaque hemorrhage, to plaque progression. Disruption of a vulnerable or unstable plaque (type IV and Va lesions of the AHA classification) with a subsequent change in plaque geometry and thrombosis may result in an acute coronary syndrome. The high-risk plaque tend to be relatively small, but soft or vulnerable to "passive" disruption because of high lipid content. Inflammatory processes are important components of all stages of atherosclerotic development, including plaque initiation and disruption. As such the early steps in atherosclerotic lesion formation are the over expression of endothelial adhesive protein (i.e. selectins, VCAM and ICAM), chemotactic factors (MCP-1), growth factors (M-CSF), and cytokines (IL-2) that will facilitate the recruitment, internalization and survival of blood-borne inflammatory cells into the vascular wall. Macrophages, following what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with release of MMPs and TF. Specific cell recruitment in the vessel wall and build-up of the extracellular matrix are coordinated by a wide variety of stimulators and inhibitors. Active interaction of immune competent cells within the atherosclerotic lesions appears to play a pivotal role in the control of atherosclerotic plaque evolution and, therefore, deserves particular attention from the research community with the ultimate goal of improving preventive and therapeutic medical approaches. Inflammation, thrombosis and atherosclerosis are interdependent and define a triad within the complex pathogenic process of atherothrombosis.
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PMID:Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis. 1527 86

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
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PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

Atherosclerosis is generally considered an inflammatory disease characterized by the accumulation of lipid in large and medium elastic arteries. Individuals who smoke are at increased risk for developing atherosclerosis and the clinical events associated with this disease. Underlying the mechanisms involved in atherosclerotic lesion development exists a complex pattern of signaling, involving molecules (cytokines and chemokines) that mediate the progression of arterial lesions. The unique nature of exposure to tobacco-related toxicants during the process of smoking prompted our investigation of the time-dependent responses of two critical cell types to cigarette smoke condensate exposure. In this study, we examined the kinetic responses, using suspension array technology and RT-PCR of 17 cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17 GM-CSF, G-CSF, INF-gamma, TNF-alpha, MCP-1 and MIP-1beta) in human aortic endothelial cells (HAECs) and THP-1 monocyte macrophages following exposure to cigarette smoke condensate (CSC) for 24h. In HAECs, IL-8 and IL-4 were rapidly stimulated by CSC exposure while, surprisingly, MCP-1 expression was downregulated. In THP-1 macrophages, IL-6, MIP-1beta, MCP-1 and IL-1beta protein expression were suppressed upon CSC exposure. All other measurable cytokines in THP-1 cells exposed to CSC had levels of protein and mRNA similar to controls. Depending on cell type, CSC uniquely influences the expression of cytokines. The complex interplay of these signaling molecules within the framework of atherosclerosis points to the ability of cigarette smoke components to alter such signaling following acute exposure, and by this mechanism may alter the course of both atherogenesis initiation and progression.
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PMID:Kinetic analysis of cytokine response to cigarette smoke condensate by human endothelial and monocytic cells. 1588 68

Early growth response factor-1 (Egr-1) is a zinc-finger transcription factor that induces genes that promote atherosclerosis. The goal of the present study was to determine whether Egr-1 expression is modulated by atherogenic, triglyceride rich lipoproteins known as chylomicron remnants. Chylomicron remnants induced Egr-1 mRNA and protein expression in rat cultured vascular smooth muscle cells (VSMCs) and activated extracellular signal-regulated kinase (ERK) 1/2 in VSMCs. Further, chylomicron remnant-induced Egr-1 expression was inhibited by PD98059, a selective inhibitor of MAPK kinase (MEK), suggesting that the action of chylomicron remnants on Egr-1 was dependent on the ERK/MEK pathway. Chylomicron remnants also induced mRNA expression of the pro-inflammatory cytokines, IL-2 and IFN-gamma in VSMCs. We conclude that chylomicron remnants act as atherogenic lipoproteins via induction of Egr-1 expression and via cytokine-mediated inflammation.
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PMID:Chylomicron remnants regulate early growth response factor-1 in vascular smooth muscle cells. 1592 98

The study included measurement of serum levels of IL-1beta, IL-2, IL-6, IL-8, and TNF-alpha, as well as the expression of mRNA IL-1beta, IL-2, IL-6, and TGfb1 in the vascular wall of patients with coronary atherosclerosis (angina, myocardial infarction). IL-1beta, IL-2, IL-6, IL-8, and TNF-alpha serum levels in patients with coronary atherosclerosis were found to significantly higher than those in healthy individuals (control group). Detection of IL-1beta, IL-2, IL-6, and TGFb1 in tissues revealed mRNA of the cytokines under study in radial artery wall. The main aortic cytokine was found to be IL-2 (7 samples out of 8); the main cytokines in peripheral arteries were IL-1beta and IL-6 (5 samples out of 8). The results show that elevation of IL-1beta, IL-2, and IL-8 in patients with coronary atherosclerosis demonstrates an immunoinflammatory nature of the disease; the detection of dissimilar cytokines in tissue samples reflects not only different degree of vessel involvement, but also a phase character of the process.
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PMID:[Immunological interactions in different forms of coronary heart disease]. 1610 16

Fish oils supplementation has been recently widely used in prevention and treatment of the diseases in humans. Fish oil beneficial effects have been investigated in a number of animal disease models as well as human studies. Here, we examined clinical, immunological and biochemical effects of shark liver oil supplementation in high doses in 13 volunteers. The experiment was based on the consumption of 3.6 g of squalene, 3.6 g of alkylglycerols and 750 mg of n-3 polyunsaturated fatty acids (PUFA) per day for 4 weeks. We have shown the increased response of neutrophils towards bacteria, the increased level of C4 component of complement in blood, the rise of total antioxidant status of serum, and the predominance of Type I cytokine IFN-gamma, TNF-alpha and IL-2 production by peripheral blood mononuclear cells after shark liver oil intake. Moreover, shark liver oil supplementation markedly affect lipid metabolism and cholesterol balance. The increase of total cholesterol level from 182.92 +/- 29.290 mg/dl before oil consumption to 224.46 +/- 62.198 mg/dl after diet rich in oil, and the decrease of HDL fraction were noted. However, metabolism of lipids normalised spontaneously after the end of the experiment in all the individuals. The results of the present study have shown, that the main effects of shark liver oil are the result of the biological activity of squalene and 1-O-alkylglycerols, which dominate in the composition of the oil quantitatively. On the contrary, anti-inflammatory effects of n-3 PUFA do not manifest, when taking together with high doses of squalene and alkylglycerols. On the bases of these observations, we propose that shark liver oil supplementation in high doses is beneficial in bacterial, viral and fungal infections, whereas patients with atherosclerosis or autoimmune diseases should avoid the consumption of high amounts of shark liver oil.
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PMID:[Effect of high doses of shark liver oil supplementation on T cell polarization and peripheral blood polymorphonuclear cell function]. 1612 84

Increased mortality due to cardiovascular disease in rheumatoid arthritis (RA) patients was reported. Using B-mode ultrasonography we compared intima-media thickness (IMT) and plaque occurrence (indicators of asymptomatic atherosclerosis) in the carotid arteries in 70 pre-menopausal, female RA patients and 40 controls. Correlations with different risk factors were evaluated. The IMT values were higher in RA patients (0.59 mm vs. 0.47 mm, P < 0.0001) and they had more plaques (P = 0.023). In RA patients higher levels of sensitive CRP (P < 0.0001), ICAM (P < 0.0001), VCAM (P < 0.0001), IL-2 (P < 0.001), IL-6 (P = 0.009) and TNF-alfa (P < 0.01) were found. A correlation between IMT and triglycerides (P = 0.018) and a negative correlation between IMT and HDL cholesterol (P = 0.037) were found. With multiple regression analysis the association between IMT and sensitive CRP (P = 0.027) and presence of plaques and apolipoprotein B (P = 0.028) was established. The results indicate that even pre-menopausal, female RA patients had accelerated atherosclerosis. Chronic systemic inflammation may play an important role in atherogenesis.
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PMID:Accelerated atherosclerosis in pre-menopausal female patients with rheumatoid arthritis. 1695 96


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