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 mechanisms of increased expression of toll-like receptor 4 (TLR-4) during the formation of foam cells were explored. Low density lipoprotein (LDL) was prepared by density gradient ultracentrifugation and oxidized by incubation with CuCl2. The human monocytic leukemia cell line (THP-1) was cultured in RPMI1640. The differentiation of THP-1 cells into macrophages (MPs) was induced by using myristate acetate (PMA) for 48 h. The macrophages were then incubated with oxidized LDL (ox-LDL) to generate foam cells (FCs). The mRNA and protein expression levels of human TLR-4 were detected by immunocytochemistry, Western blotting and reverse transcription polymerase chain reaction (RT-PCR). The results showed that the TLR-4 mRNA and the protein expression levels were significantly increased during the differentiation of monocytes into macrophages (P < 0.05) as well as during the formation of lipid-laden foam cells (P < 0.05). It was concluded that the upregulation of human TLR-4 gene expression during the differentiation of monocytes into macrophages and the differentiation of macrophages into foam cells could increase TLR-4 protein synthesis dramatically, which may enhance the ability of foam cells inflammation reaction in atherosclerosis.
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PMID:Mechanisms of increased expression of toll-like receptor-4 in human monocyte/macrophage-derived foam cells. 1646 49

The toll-like receptor 4 gene product (TLR4) has been implicated in the pathogen recognition response mechanism because it plays a central role in the transcriptional activation of the host defense system. Activation of TLR4 initiates an intracellular signaling cascade, via the adapter protein MyD88 (myeloid differentiation factor 88), which leads to the activation of NF-kappaB transcriptional factor, and ultimately to the induction of a pro-inflammatory response. This inflammatory response has been increasingly associated with atherosclerosis. Recent analyses on two polymorphisms of TLR4, which affect the extracellular domain of the receptor, have been shown to give rise to an attenuated innate immune defense which may contribute to disease susceptibility. We have investigated the significance of four new substitutions found by re-sequencing in the 5'-proximal promoter region of the TLR4 gene in a case-control study of acute myocardial infarction. Our results found no statistically significant association between these genetic variants and MI.
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PMID:The lack of association between four point mutations in the promoter region of the toll-like 4 receptor gene and myocardial infarction. 1646 62

A nuclear protein, high mobility group box 1 (HMGB1), is released passively by necrotic cells, and actively by macrophages/monocytes in response to exogenous and endogenous inflammatory stimuli. After binding to the receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4), HMGB1 activates vascular endothelial cells and macrophages/monocytes to express proinflammatory cytokines, chemokines and adhesion molecules. Pharmacological suppression of its activities or release is protective against lethal endotoxemia and sepsis, establishing HMGB1 as a critical mediator of lethal systemic inflammation. In light of the pathogenic role of inflammation in cardiovascular diseases, we propose that HMGB1, a proinflammatory cytokine derived from both injured endothelium and activated macrophages/monocytes, could contribute to the progression of atherosclerosis and other cardiovascular diseases.
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PMID:Role of HMGB1 in cardiovascular diseases. 1648 50

Cardiovascular diseases (CVD), such as myocardial infarction (MI), are major causes of disability and mortality in the elderly. The increasing burden of CVD in ageing industrialized populations requires intensive research in order to improve preventive and therapeutic strategies especially in old people and if possible slow the processes of cardiovascular disease generation and progression. Ageing is accompanied by an age-dependent up-regulation of the inflammatory response, due to chronic antigenic stress stimulation, which potentially triggers the onset of inflammatory diseases, especially CVD. However, the exact mechanisms are still poorly understood. Since CVD are caused by interactions between genetic and environmental factors, a possible approach to their prevention is to identify the potential genetic component of inflammatory cardiovascular risk factors, providing the basis for personalized lifestyle modification and improved pharmacological therapy. Some common gene polymorphisms associated with high production of inflammatory molecules have been associated with atherosclerosis. Therefore, controlling inflammation might play a protective role against CVD, especially in ageing. Although a large number of studies of pro- and anti-inflammatory gene variants in association with CVD and MI exists, the emerging data are quite conflicting and do not provide definitive evidence for a role of these polymorphisms in the pathogenesis of MI. In this paper we review the evidence for a possible role of genetic polymorphisms of the most important inflammatory cytokines (IL-6, TNF-alpha, IL-10) and immune receptors (CD14 receptor and TLR-4) in modulating the incidence or the prognosis of MI, with a special focus in ageing population.
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PMID:Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly. 1651 51

Mammalian cells respond to bacterial lipopolysaccharide (LPS) through a cognate receptor: Toll-like receptor 4 (TLR4). The signaling pathways, which link TLR4 to the proinflammatory transcription factor nuclear factor kappaB (NF-kappaB), occur through the intracellular docking proteins MyD88 and Trif. We hypothesize that unlike antigen-presenting cells, vascular endothelial cells (ECs) lack the Trif protein TRAM and are therefore incapable of eliciting Trif-dependent immune responses to LPS. Stimulation of wild-type mice with LPS leads to the activation of NF-kappaB in ECs and macrophages in vitro and in vivo. In contrast to macrophages, LPS did not activate endothelial NF-kappaB or NF-kappaB-dependent genes in MyD88(-/-) mice, suggesting the absence of a functional Trif pathway in vascular ECs. Indeed, the Trif-dependent gene cxcl10 was not expressed in ECs after LPS stimulation. This correlated with diminished expression of the Trif accessory TIR protein TRAM in ECs. Overexpression of TRAM cDNA in ECs reconstituted LPS-induced Trif-dependent NF-kappaB activation and cxcl10 promoter activity. The functional absence of TRAM in vascular ECs restricts TLR4 signaling to MyD88-dependent pathway. This is in contrast to macrophages, which respond to LPS via both Trif- and MyD88-dependent pathways. These findings indicate that vascular ECs do not express the Trif-dependent gene subset. This implies that these genes may be dispensable for the endothelial response to bacterial infection and play no role in the endothelial contribution to the development of atherosclerosis.
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PMID:Absence of TRAM restricts Toll-like receptor 4 signaling in vascular endothelial cells to the MyD88 pathway. 1657 2

The total burden of infection at various sites may affect the progression of atherosclerosis, the risk being modulated by host genotype. The role of lipopolysaccaride receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria; and TLR4 polymorphisms, as ASP299GLY, suggested to attenuate receptor signaling, have been described. We demonstrated that TLR4 ASP299GLY polymorphism shows a significantly lower frequency in patients affected by myocardial infarction compared to controls, whereas centenarians show a higher frequency. Thus, people genetically predisposed to developing weak inflammatory activity, seem to have fewer chances of developing cardiovascular diseases (CVD) and, subsequently, live longer if they do not become affected by serious infectious diseases. These results are in agreement with our other data demonstrating how genetic background may exert the opposite effect with respect to inflammatory components in CVD and longevity. In the present report, to validate this hypothesis, the levels of interleukin (IL)-6, a pro-inflammatory cytokine involved in atherosclerosis and longevity, were determined by an enzyme-linked immuno-sorbent assay (ELISA) in supernatants from a whole blood assay after stimulation with subliminal doses of lipopolysaccaride (LPS) from Escherichia coli (E. coli). The samples, genotyped for the ASP299GLY polymorphism, were challenged with LPS for 4, 24, and 48 h. What we found was that Il-6 values were significantly lower in carriers bearing TLR4 mutation. Therefore, the pathogen burden, by interacting with host genotype, determines the type and intensity of the immune-inflammatory responses accountable for pro-inflammatory status, CVD, and unsuccessful aging. On the other hand, our present data seem to explain the inconclusive results obtained in case-control studies taking into account the role of functional IL-6 polymorphisms in successful and unsuccessful aging. In fact, IL6 levels seem to depend, in addition, on IL-6 polymorphisms and on innate immunity gene polymorphisms as well.
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PMID:Inflammation, longevity, and cardiovascular diseases: role of polymorphisms of TLR4. 1680 99

Lipid mediators such as prostaglandin E2 (PGE2) play a central role during atherogenesis as a consequence of inflammation. PGE2 is produced from phospholipids by a cascade of enzymatic reactions involving phospholipase A2 (PLA2), cyclooxygenase (COX), and prostaglandin E synthase (PGES). It is released by several cell types, including vascular smooth muscle cells (VSMCs). Recent work has shown that the secretory PLA2-IIA (sPLA2-IIA), the most abundant isoform of secreted PLA2 in VSMCs, acts as a potent cytokine and activates VSMCs through a positive feedback loop. High mobility group protein 1 (HMGB1), also known as amphoterin, is a ubiquitous protein that plays various roles in the nucleus. HMGB1 is released by necrotic cells and by immune cells in response to various inflammatory mediators and acts as a potent proinflammatory cytokine. The present study investigates the role of HMGB1 in the activation of sPLA2-IIA expression and PGE2 production in VSMCs. Recombinant HMGB1 slightly activated the sPLA2-IIA, COX-2, and mPGES-1 genes but dramatically stimulated these genes in VSMCs that had been incubated with the proinflammatory cytokine IL-1beta for 24 h. This effect was accompanied by significantly increased PGE2 release. Induction of the three known receptors of HMGB1, namely RAGE, TLR-2, and TLR-4, by IL-1beta suggests that proinflammatory cytokines sensitize VSMCs to HMGB1. This provides new insights into the role of HMGB1 in VSMCs, suggesting it may be essential for the progression of atherosclerosis.
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PMID:Activation of sPLA2-IIA and PGE2 production by high mobility group protein B1 in vascular smooth muscle cells sensitized by IL-1beta. 1680 71

Heat shock proteins (HSPs) of endogenous and exogenous origin are suspected contributors to the initiation and aggravation of vascular pathologies like atherosclerosis and restenosis. Toll-like receptors (TLRs) 2 and 4 are well-known receptors for exogenous pathogen-associated molecular patterns and have recently been thought to play a role in HSP60-induced cellular activation. We hypothesized that human HSP60 directly stimulates venous smooth muscle cell (VSMC) proliferation through a TLR-dependent mechanism. Localization of HSP60, TLR2 and TLR4 was studied in failed venous grafts and normal venous tissue by double immunostaining. In vitro VSMCs were incubated for 48 h with recombinant human HSP60. In other experiments, VSMCs were pre-incubated for 30 min with specific anti-TLR2 and anti-TLR4 antibodies. VSMC proliferation was determined by Ki67 immunoreactivity, and mean values were compared between experimental and control groups. In addition, human embryonic kidney (HEK) cells transfected with human TLR2 or TLR4/MD-2 were exposed to HSP60 for 48 h, and proliferation was determined by using a hemocytometer. Co-localization of HSP60 and TLRs was detected in all neointimal lesions but was virtually absent in normal veins. Human HSP60 stimulated VSMC proliferation in a concentration-dependent fashion. In addition, TLR2 and TLR4 antibodies attenuated VSMC proliferation. The role of TLR-mediated stimulation of cell proliferation by HSP60 was supported by the significant increase in proliferation of transfected HEK cells. These findings provide supporting evidence for the role of HSP60 and TLR2 and TLR4 in vascular disease. Moreover, our data surpass the infection- and autoimmunity-based hypotheses of cardiovascular disease and suggest an additional HSP60-related autocrine process.
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PMID:Human heat shock protein 60 stimulates vascular smooth muscle cell proliferation through Toll-like receptors 2 and 4. 1684 93

CXCL16 is a transmembrane non-ELR CXC chemokine that signals via CXCR6 to induce aortic smooth muscle cell (ASMC) proliferation. While bacterial lipopolysaccharide (LPS) has been shown to stimulate CXCL16 expression in SMC, its effects on CXCR6 are not known. Here, we demonstrate that LPS upregulates CXCR6 mRNA, protein, and surface expression in human ASMC. Inhibition of TLR4 with neutralizing antibodies or specific siRNA interference blocked LPS-mediated CXCR6 expression. LPS stimulated both AP-1 (c-Fos, c-Jun) and NF-kappaB (p50 and p65) activation, but only inhibition of AP-1 attenuated LPS-induced CXCR6 expression. Using dominant negative expression vectors and siRNA interference, we demonstrate that LPS induces AP-1 activation via MyD88, TRAF6, ERK1/2, and JNK signaling pathways. Furthermore, the flavoprotein inhibitor diphenyleniodonium chloride significantly attenuated LPS-mediated AP-1-dependent CXCR6 expression, as did inhibition of NOX4 NADPH oxidase by siRNA. Finally, CXCR6 knockdown inhibited CXCL16-induced ASMC proliferation. These results demonstrate that LPS-TLR4-NOX4-AP-1 signaling can induce CXCR6 expression in ASMC, and suggest that the CXCL16-CXCR6 axis may be an important proinflammatory pathway in the pathogenesis of atherosclerosis.
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PMID:TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells. 1687 Jan 45

Infection and innate immunity have been suggested as playing an important role in the pathogenesis of atherosclerosis. The recently discovered pattern-recognition receptor (PRR) proteins initiate signalling after host-pathogen interactions and several PRRs, especially the Toll-like receptor 4 (TLR4), have been shown to be involved in the development and progression of atherosclerosis. A new addition to the PRRs is CARD4, a gene that encodes the protein nucleotide-binding oligomerization domain 1 (NOD1) and that seems to be associated with barrier function in chronic inflammatory disorders. Recently, a functional variant in the CARD4 gene, the insertion-deletion polymorphism ND(1)+32656, has been associated with inflammatory barrier diseases (inflammatory bowel diseases and asthma). We analysed the frequencies of this known functional mutation in the CARD4 gene and of the two adjacent variants, rs2075822 and rs2907748, in a German sample of 1440 unrelated early onset coronary heart disease (CHD) patients and healthy controls. Genotype and haplotype data showed no evidence for a significant association of these CARD4 variants with CHD. Our results suggest that the analysed CARD4 mutations do not play a major role in the aetiology of CHD.
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PMID:A functional variant in the CARD4 gene and risk of premature coronary heart disease. 1689 97


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