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)

C-reactive protein (CRP) has been suggested to directly induce the inflammatory response leading to the progression of atherosclerosis. However, recent in vitro studies raised the possibility that the effects of CRP are caused by biologically active contaminants such as sodium azide and endotoxin. In this study, we tested whether azide- and endotoxin-free CRP induces endothelial cell apoptosis and production of proinflammatory mediators. In human endothelial cells, CRP significantly inhibited cell proliferation and increased endothelial cell apoptosis evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and caspase-3 activity assay, which is reversed by a function-blocking antibody to Fc gamma RIIIB by 78%. Western blot analysis showed that CRP significantly attenuated flow-mediated activation of Akt, a key molecule for endothelial cell survival pathways. In human mononuclear cells, CRP-induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and matrix metalloproteinase-9 (MMP-9) in a concentration-dependent manner. This CRP-induced MMP-9 production was significantly inhibited by function-blocking antibodies to TNF-alpha, IL-1 beta, and Fc gamma RIIA. These findings suggest that CRP itself induces endothelial cell apoptosis and production of proinflammatory mediators. Because endothelial cell apoptosis and MMP-9 production are critical for the destabilization of atherosclerotic plaque, this study may provide insight into a role of CRP in the development of plaque rupture.
Atherosclerosis 2008 Jan
PMID:C-reactive protein induces endothelial cell apoptosis and matrix metalloproteinase-9 production in human mononuclear cells: Implications for the destabilization of atherosclerotic plaque. 1753 Dec 42

Lysophosphatidic acid (LPA), a low-molecular-weight lysophospholipid enriched in platelets and mildly oxidized low-density lipoproteins, is known to regulate inflammation and atherosclerosis by binding to its cognate receptors. In this study, we reported that LPA upregulated interleukin-1 beta (IL-1 beta) expression in mouse J774A.1 macrophages. By using pharmacological inhibitors, it was suggested that G(i)/Rho activation and subsequent reactive oxygen species (ROS) production were involved in IL-1 beta induction. In addition, IL-1 beta induction by LPA was also observed in human primary macrophages. In summary, LPA is involved in the processes of inflammation by affecting macrophage behavior.
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PMID:Lysophosphatidic acid-induced interleukin-1 beta expression is mediated through Gi/Rho and the generation of reactive oxygen species in macrophages. 1803 69

Donkey's milk is the best substitute of human milk for its content in lactose, proteins, minerals, and omega-3 fatty acids. Here, we have evaluated the effects of colostrum and milk from donkeys (Martina Franca breed) on the function of human peripheral blood mononuclear cells (PBMCs) at different intervals from lactation. Colostrum induced more IgA responses, while milk induced predominantly more IgG responses. Both milk and colostrum induced expression of CD25 and CD69 on PBMCs. The ability to induce release of interleukins (IL) (IL-12, IL-1 beta and IL-10) and tumor necrosis factor-alpha was confined only to milk, while colostrum was devoid of this capacity. Finally, both colostrum and milk induced nitric oxide (NO) release from PBMCs but milk exhibited a greater capacity than colostrum in NO generation. Taken together, these immunological activities exerted by both colostrum and milk from donkeys may be useful in the treatment of human immune-related diseases. In particular, NO induction by donkey's milk may be very useful in the prevention of atherosclerosis, being a strong vasodilator and an effective antimicrobial agent since pathogens and/or their products may play a proatherogenic role.
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PMID:Immunological properties of donkey's milk: its potential use in the prevention of atherosclerosis. 1822 Aug 10

A high omega-6/omega-3 ratio, as is found in today's Western diets, promotes the pathogenesis of many chronic diseases, including cardiovascular disease. Increased dietary intake of linoleic acid (LA) leads to oxidation of low-density lipoprotein (LDL), platelet aggregation, and interferes with the incorporation of essential fatty acids (EFA) in cell membrane phopholipids. Both omega-6 and omega-3 fatty acids influence gene expression. Omega-3 fatty acids have strong anti-inflammatory effects, suppress interleukin 1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6), whereas omega-6 fatty acids tend to be pro-inflammatory. Because inflammation is at the base of many chronic diseases, including coronary heart disease, dietary intake of omega-3 fatty acids plays an important role in the manifestation of disease, particularly in persons with genetic variation, as for example in individuals with genetic variants at the 5-lipoxygenase (5-LO). Increased dietary arachidonic acid (AA) significantly enhances the apparent atherogenic effect of genotype, whereas increased dietary intake of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) blunts this effect. The diet-gene interaction further suggests that dietary omega-6 fatty acids promote, whereas marine omega-3 fatty acids EPA and DHA inhibit leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation.
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PMID:The omega-6/omega-3 fatty acid ratio, genetic variation, and cardiovascular disease. 1829 20

Recent diabetes control and complications trial and epidemiology of diabetes interventions and complications (DCCT/EDIC) and other clinical studies have reported that glucose control in patients with diabetes leads to a significant reduction of cardiovascular events and atherosclerosis, indicating that hyperglycemia plays an essential role in cardiovascular disease in diabetic patients. Although several mechanisms by which hyperglycemia promotes atherosclerosis have been proposed, it remains unclear how hyperglycemia promotes atherosclerosis by interaction with inflammatory cytokines. To test our hypothesis that hyperglycemia interplays with interferon gamma (IFN gamma), a key factor involved in atherosclerosis, to up-regulate the expression of genes such as matrix metalloproteinases (MMPs) and cytokines that are involved in plaque destabilization, U937 macrophages cultured in medium containing either normal or high glucose were challenged with IFN gamma and the expression of MMPs and cytokines were then quantified by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Results showed that high glucose and IFN gamma had a synergistic effect on the expression of MMP-1, MMP-9 and IL-1 beta. High glucose also enhanced IFN gamma-induced priming effect on lipopolysaccharide (LPS)-stimulated MMP-1 secretion. Furthermore, high glucose and IFN gamma exert the synergistic effect on MMP-1 expression by enhancing STAT1 phosphorylation and STAT1 transcriptional activity. In summary, this study revealed a novel mechanism potentially involved in diabetes-promoted cardiovascular disease.
Atherosclerosis 2009 Feb
PMID:High glucose and interferon gamma synergistically stimulate MMP-1 expression in U937 macrophages by increasing transcription factor STAT1 activity. 1858 52

Increased circulating free fatty acids in subjects with type 2 diabetes may contribute to activation of macrophages, and thus the development of atherosclerosis. In this study, we investigated the effect of the saturated fatty acids (SFA) palmitate, stearate, myristate and laurate, and the unsaturated fatty acid linoleate, on the production of proinflammatory cytokines in phorbol ester-differentiated THP-1 cells, a model of human macrophages. Palmitate induced secretion and mRNA expression of TNF-alpha, IL-8 and IL-1 beta, and enhanced lipopolysaccharide (LPS)-induced IL-1 beta secretion. Proinflammatory cytokine secretion was also induced by stearate, but not by the shorter chain SFA, myristate and laurate, or linoleate. Triacsin C abolished the palmitate-induced cytokine secretion, suggesting that palmitate activation to palmitoyl-CoA is required for its effect. Palmitate-induced cytokine secretion was decreased by knockdown of serine palmitoyltransferase and mimicked by C(2)-ceramide, indicating that ceramide is involved in palmitate-induced cytokine secretion. Palmitate phosphorylated p38 and JNK kinases, and blocking of these kinases with specific inhibitors diminished the palmitate-induced cytokine secretion. Palmitate also activated the AP-1 (c-Jun) transcription factor. Knockdown of MyD88 reduced the palmitate-induced IL-8, but not TNF-alpha or IL-1 beta secretion. In conclusion, our data suggest that the long-chain SFA induce proinflammatory cytokines in human macrophages via pathways involving de novo ceramide synthesis. This might contribute to the activation of macrophages in atherosclerotic plaques, especially in type 2 diabetes.
Atherosclerosis 2009 Feb
PMID:Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. 1859 66

Cortex Moutan (Paeonia suffruticosa Andrews, Ranunculaceae) has several uses in traditional medicine, such as analgesic, antipyretic, and anti-inflammatory applications and use in the prevention of thromboembolic diseases. Paeonol, a main active component in Cortex Moutan, possesses various pharmacological activities, particularly an anti-atherosclerosis effect. However, so far there have been no reports evaluating the anti-inflammatory action of paeonol in atherosclerosis therapy. The purpose of this study was to investigate the association of the therapeutic effect of paeonol on atherosclerotic rabbits with its anti-inflammatory action. The atherosclerotic model was developed in 24 rabbits fed a high-fat diet for 12 weeks. Twelve rabbits on the high-fat diet then were administered with paeonol (p.o) for a subsequent 6 weeks at the doses of 75 mg/kg and 150 mg/kg. Histological analysis showed significant improvement in atherosclerosis plaque in the paeonol groups. Moreover, the blood levels of TNF- alpha, IL-1 beta, and CRP and the translocation of NF- kappaB to the nucleus were significantly suppressed in paeonol groups, as was the inhibition of lipid peroxidation. In conclusion, these findings suggest that the anti-inflammatory action of paeonol may contribute to its anti-atherosclerosis effect.
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PMID:Paeonol attenuates high-fat-diet-induced atherosclerosis in rabbits by anti-inflammatory activity. 1900 27

Studies of human native C-reactive protein (nCRP) in mice have shown effects ranging from proatherogenic, to antiatherogenic, to no effect. It is likely that these disparities are related to (a) the use, in some studies, of contaminated nCRP, or to (b) variation in CRP levels associated with either its episodic administration or the use of CRP-transgenic mice. In our study, 12-week-old male apolipoprotein E-deficient (apoE (-/-)) mice, maintained on a Western diet, received azide- and endotoxin-free nCRP (n = 23) or placebo (n = 23) continuously via osmotic pumps (20.4 microg/day) for 4 weeks. CRP-treated and control mice developed similar atherosclerotic lesions in whole aortas (nCRP: 10.4 +/- 4.7% vs. controls: 11.7 +/- 4.4%, P = 0.76) and aortic roots (nCRP: 65.0 +/- 7.8% vs. controls: 64.7 +/- 9.7%, P = 0.94). No differences were observed in macrophage or T-lymphocyte infiltrates and there was no meaningful change in VCAM-1 or IL-6 expression, in the levels of soluble VCAM-1, or in circulating proinflammatory (IL-1 beta, IL-6, IL-12p40, IL-12p70, TNF-alpha, and INF-gamma), or anti-inflammatory (IL-4 and IL-10) cytokines. We conclude that continuous infusion of uncontaminated nCRP in apoE (-/-) mice is not associated with increased atherosclerosis, does not alter systemic or local inflammation, and does not affect endothelial activation. These observations suggest that alternative approaches to study CRP (perhaps using different pentraxins in the mouse model or using a rabbit model instead of a mouse model) are needed to evaluate the effects of pentraxins on atherosclerosis.
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PMID:Continuously-infused human C-reactive protein is neither proatherosclerotic nor proinflammatory in apolipoprotein E-deficient mice. 1935 57

The inflammatory process has been considered an important mediator for the development of atherosclerosis. Interleukin-1 beta (IL1B) is a precursor of interleukin-6 (IL6) in the acute phase of inflammatory response and their levels are elevated in patients with coronary artery disease. The aim of the present study was to further investigate the association of IL-1B and IL-6 gene polymorphisms and angiographically assessed coronary artery disease (CAD) in African- and Caucasian-Brazilians. This report analyzed the IL-1B-511C>T and IL-6-174G>C polymorphisms in 667 patients (253 African-Brazilians and 414 Caucasian-Brazilians) who underwent coronary angiography. Patients with a coronary obstructive lesion 50% presented a higher frequency of the IL-1B-511CC genotype (30.4%) compared to lesion-free individuals (16.5%, p=0.032) in African- but not in Caucasian-Brazilians. No significant genotype frequency difference was identified for the IL-6-174G>C polymorphism in either ethnic groups. However, after correction for other CAD risk factors using multivariate logistic regression, both the IL-1B-511CC [Odds ratio (OR)=2.3; p=0.019] and the IL-6-174GG (OR=2.0; p=0.028) genotypes were considered independent CAD risk predictors in African-Brazilians. This report shows that the IL-1B-511C>T and IL-6-174G>C polymorphisms were associated with CAD risk in African-Brazilians and no association was detected among Caucasian-Brazilians.
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PMID:Interleukin-1 beta and interleukin-6 gene polymorphism associations with angiographically assessed coronary artery disease in Brazilians. 2020 49

Studies in humans have established that polymorphisms in genes encoding the innate immune Toll-like receptors (TLRs) are associated with inflammatory atherosclerosis. In hyperlipidemic mice, TLR2 and TLR4 have been reported to contribute to atherosclerosis progression. Human and mouse studies support a role for the oral pathogen Porphyromonas gingivalis in atherosclerosis, although the mechanisms by which this pathogen stimulates inflammatory atherosclerosis via innate immune system activation is not known. Using a genetically defined apolipoprotein E-deficient (ApoE(-/-)) mouse model we demonstrate that pathogen-mediated inflammatory atherosclerosis occurs via both TLR2-dependent and TLR2-independent mechanisms. P. gingivalis infection in mice possessing functional TLR2 induced the accumulation of macrophages as well as inflammatory mediators including CD40, IFN-gamma and the pro-inflammatory cytokines IL-1 beta, IL-6 and tumor necrosis factor-alpha in atherosclerotic lesions. The expression of these inflammatory mediators was reduced in atherosclerotic lesions from P. gingivalis-infected TLR2-deficient (TLR2(-/-)) mice. These studies provide a mechanistic link between an innate immune receptor and pathogen-accelerated atherosclerosis by a clinically and biologically relevant bacterial pathogen.
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PMID:Pathogen-mediated inflammatory atherosclerosis is mediated in part via Toll-like receptor 2-induced inflammatory responses. 2050 14


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