Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD40 ligand (CD40L)-CD40 dyad can ignite proinflammatory and procoagulatory activities of the vascular endothelium in the pathogenesis and progression of atherosclerosis. Besides being expressed on the activated CD4(+) T cell surface (mCD40L), the majority of circulating CD40L reservoir (sCD40L) in plasma is released from stimulated platelets. It remains debatable which form of CD40L triggers endothelial inflammation. Here, we demonstrate that the agonistic antibody of CD40 (G28.5), which mimics the action of sCD40L, induces rapid endocytosis of CD40 independent of TRAF2/3/6 binding while CD40L expressed on the surface of HEK293A cells captures CD40 at the cell conjunction. Forced internalization of CD40 by constitutively active mutant of Rab5 preemptively activates NF-kappaB pathway, suggesting that CD40 was able to form an intracellular signal complex in the early endosomes. Internalized CD40 exhibits different patterns of TRAF2/3/6 recruitment and Akt phosphorylation from the membrane anchored CD40 complex. Finally, mCD40L but not sCD40L induces the upregulation of proinflammatory cytokines and cell adhesion factors in the primary human vascular endothelial cells in vitro, although both forms of CD40L activate NF-kappaB pathway. These results therefore may help understand the molecular mechanism of CD40L signaling that contributes to the pathophysiology of atherosclerosis.
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PMID:Internalization of CD40 regulates its signal transduction in vascular endothelial cells. 1667 4

Originally designed to target elevated lipids, the "traditional" cause of atherosclerosis, statins might also confer vascular benefit by directly or indirectly modulating both the inflammatory and immune responses. Statins have been shown to downregulate MHC class II and CD40 expression on activated endothelial cells (EC). In this study, we investigate the potential effect of statins on MHC class I expression and regulation in response to IFNgamma. Primary cultures of human ECs have been treated with increasing doses of fluvastatin (0.01; 0.1 and 1 microM) with or without IFNgamma for 48 hours. Surface expression of MHC class I and class II has been analyzed by flow cytometry. Our data indicate that fluvastatin increases MHC class I expression on quiescent ECs by a dose-dependent effect. Furthermore, fluvastatin potentiates the MHC class I upregulation but prevents MHC class II induction triggered by IFNgamma. These effects are reversed by mevalonate. In conclusion, our results suggest that while decreasing MHC class II expression, fluvastatin (at 0.1 and 1 microM) upregulates MHC class I expression on ECs. Functional consequences of statin-mediated modulation of MHC on ECs have still to be elucidated in vitro and in vivo.
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PMID:[Fluvastatin affects HLA class I expression on endothelial cells]. 1689 88

Hyperlipidemia enhances xanthine oxidase (XO) activity. XO is an important source of reactive oxygen species (ROS). Since ROS are thought to promote atherosclerosis, we hypothesized that XO is involved in the development of atherosclerosis. ApoE(-/-) mice were fed a Western-type (WD) or control diet. In subgroups, tungsten (700 mg/L) was administered to inhibit XO. XO is a secreted enzyme which is formed in the liver as xanthine dehydrogenase (XDH) and binds to the vascular endothelium. High expression of XDH was found in the liver and WD increased liver XDH mRNA and XDH protein expression. WD induced the conversion of XDH to the radical-forming XO. Moreover, WD increased the hepatic expression of CD40, demonstrating activation of hepatic cells. Aortic tissue of ApoE(-/-) mice fed a WD for 6 months exhibited marked atherosclerosis, attenuated endothelium-dependent relaxation to acetylcholine, increased vascular oxidative stress, and mRNA expression of the chemokine KC. Tungsten treatment had no effect on plasma lipids but lowered the plasma XO activity. In animals fed a control diet, tungsten had no effect on radical formation, endothelial function, or atherosclerosis development. In mice fed a WD, however tungsten attenuated the vascular superoxide anion formation, prevented endothelial dysfunction, and attenuated KC mRNA expression. Most importantly, tungsten treatment largely prevented the development of atherosclerosis in the aorta of ApoE(-/-) mice on WD. Therefore, tungsten, potentially via the inhibition of XO, prevents the development of endothelial dysfunction and atherosclerosis in ApoE(-/-) mice on WD.
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PMID:Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet. 1702 62

Unlike diabetes mellitus and impaired glucose tolerance, it is not clear whether the subjects with impaired fasting glucose (IFG) are at increased risk of atherosclerosis and cardiovascular diseases. The CD40-CD40 ligand interaction is involved in the mechanism of atherosclerosis. We investigated whether soluble CD40L (sCD40L) as well as high sensitive C-reactive protein (hsCRP) levels are increased in subjects with IFG having no confounding factors for inflammation or atherosclerosis. Twenty four IFG subjects with no additional disorders and 40 appropriate healthy controls were studied. sCD40L and hsCRP levels in the IFG and control groups were similar. Blood pressures, total and LDL-cholesterol, and triglyceride levels were also similar, whereas HDL-cholesterol was lower and HOMA-IR indexes were higher in the IFG group. Though the sample size was small, the present data show that sCD40L seems not to alter in subjects with IFG suggesting that it might not be an independent risk factor for atherosclerosis.
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PMID:Soluble CD40 ligand levels in otherwise healthy subjects with impaired fasting glucose. 1739 73

The main goal of therapy for lupus nephritis is to achieve remission, as this has a major impact on patient and renal survival. Furthermore, early treatment success has been shown to improve long-term prognosis. This has traditionally been achieved with intravenous cyclophosphamide, but recent data show that mycophenolate mofetil is equally effective and causes fewer adverse effects. Research is ongoing to find new treatment targets. Possible future therapies include monoclonal antibodies against CD20 (rituximab), CD22 (epratuzumab) and CD40, and therapies targeted at cytokine secretion, immunoglobulin secretion, B-cell maturation and T-cell proliferation and differentiation. Rituximab has shown promise in patients with active proliferative lupus nephritis, which suggests that B-cell depletion may be successful. Anti-double-stranded DNA antibodies correlate with flares of lupus nephritis and may represent another therapeutic target. Therapy with LIP 394, which crosslinks anti-double-stranded DNA antibodies in solution or on the B-cell surface, has been shown to reduce flares. Cardiovascular disease is a major cause of mortality in systemic lupus erythematosus, and this must also be addressed if long-term outcomes are to be improved. Many patients with systemic lupus erythematosus have subclinical atherosclerosis quite early in the disease course, and the risk of coronary artery disease at any level of traditional cardiovascular risk factors is higher than in the general population. Specific lupus-associated risk factors include the inflammatory process itself and anticardiolipin antibodies. Possible strategies to reduce the risk include reduction of disease activity to improve endothelial function and reduction of steroid dose whenever possible. Therapy with aspirin or statins may be another possibility. Thus treatment of lupus nephritis is evolving from standardised therapy to individualised therapy based on analysis of organ involvement, risk factors and cytokine, antibody or cell profiles.
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PMID:Exploring new territory: the move towards individualised treatment. 1743 12

CD40-CD40 ligand (CD40L) interactions play a central role in the development and progression of atherosclerosis. In the late 1990s, we and others have shown that complete inhibition of the CD40L signaling pathway resulted in a decrease in atherosclerosis and in the induction of a stable atherosclerotic plaque phenotype. These stable plaques contained high amounts of collagen and vascular smooth muscle cells, whereas the amount of macrophages and T lymphocytes was low. Because clinical complications of atherosclerosis are mostly the result of plaque rupture, induction of plaque stability would significantly reduce the morbidity and mortality of atherosclerosis and thus validates inhibition of the CD40L system as a therapeutic target for atherosclerosis. However, long-term inhibition of this system probably compromises the immune system of the patient. Therefore, it is desirable to target either the downstream signaling modulators of the CD40-CD40L system that are associated with atherosclerosis, or target the CD40-CD40L system in a local, cell type-specific way. This is likely to induce plaque stabilization with limited systemic side effects, and a significant reduction of cardiovascular disease.
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PMID:CD40 and its ligand in atherosclerosis. 1748 93

In order to investigate the expression of CD40 in endothelial cells (ECs) in a variety of injured conditions and the interventional role of Andrographitis Paniculata isolate (API(0134)), the thoracic aorta ECs of guinea pigs were cultured in vitro until the third passage, incubated in the presence of media containing xanthine oxidase (XO) and xanthine (Xan) which produced oxygen free radical (OFR group); oxidized-LDL (ox-LDL group); XO, Xan and API(0134) (OFR+API(0134) group); or ox-LDL and API(0134) (ox-LDL+API(0134) group). The expression of CD40 in ECs was detected by immunofluorescence assay and reverse transcription-PCR (RT-PCR). The results showed as compared with the control group, the expression of CD40 in ECs in OFR group and ox-LDL group was increased (P<0.01), but attenuated significantly in OFR+ API(0134) group and ox-LDL+API(0134) group (P<0.05). It was suggested that API(0134) could protect atherosclerosis by inhibiting the expression of CD40 molecule in injured ECs.
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PMID:Effects of Andrographitis Paniculata extracts on the expression of CD40 in endothelial cells. 1749 79

During the early phase of atherosclerosis, T cells and monocytes attach to and migrate through the endothelium into the vessel wall. To provide an insight into the potential cross talk between T cells and smooth muscle cells (SMC) in atherogenesis, we investigated changes in gene expression caused by CD40 ligation in cultured vascular SMC and their consequences for monocyte activation. CD40 expression in human-cultured SMC was induced by 24-h treatment with tumor necrosis factor-alpha plus interferon-gamma followed by 12-h exposure to mouse myeloma cells stably expressing human CD154 or the corresponding control cells. DNA microarray analysis (Affymetrix HG-U952A chip) indicated 33 up-regulated genes in three individual experiments of which 19 encoded pro-inflammatory adhesion molecules, cytokines, chemokines, and receptors. One functional consequence of this change in gene expression was an activation of transformed human promonocytic-1 monocytes exposed to the conditioned medium of the stimulated SMC. Subsequent antibody neutralization experiments identified granulocyte-macrophage colony-stimulating factor (GM-CSF) as the SMC-derived cytokine responsible for this effect. Thus, vascular SMC-like endothelial cells appear to contribute to the maintenance of an inflammatory response in the atherosclerotic vessel wall upon CD40-CD154 co-stimulation. Among 19 up-regulated pro-inflammatory gene products, GM-CSF plays an important role in SMC-dependent monocyte activation.
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PMID:CD154-stimulated GM-CSF release by vascular smooth muscle cells elicits monocyte activation--role in atherogenesis. 1761 39

Recombinant human soluble CD40 ligand, also named CD145 or gp 39, is a 16.3 kD glycoprotein containing 149 aa residues comprising the receptor binding TNF-like domain of CD40 ligand. It is expressed on antigen-presenting cells such as B cells, macrophages, dendritic cells and thymic epithelial cells and it constitutes the nexus between the inflammatory system and the vascular thrombotic processes. Its gene is located in the long arm of the human X chromosome. Prognostic evaluation of the residual fixed atherosclerotic plaque is insufficient to predict clinical course. Currently, studies have been done that demonstrate the participation of the immunoinflammatory system in the genesis and complications of the atherosclerotic condition. In the future, the most specific biomarkers of vulnerability will be very useful in the daily practice (interleukins, CD40, etc.). The soluble CD40 ligand together with its CD40 receptor are overexpressed in experimental and human atherosclerotic lesions. This leads to an increase of mediators for the development of atherosclerosis. Both significantly contribute to the inflammatory processes that leads to atherosclerosis and thrombosis.
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PMID:[Soluble CD40 ligand: a potential marker of cardiovascular risk]. 1768 74

Atherosclerosis is considered a low-grade inflammatory disease. Polyphenol-rich alcoholic beverages (red wine) have shown a more pronounced antiinflammatory effect than polyphenol-free alcoholic beverages (gin). However, no studies to our knowledge have evaluated the antiinflammatory effects of alcoholic beverages with medium-level polyphenol content such as cava (sparkling wine). We enrolled 20 healthy men (aged 34 +/- 9 y) in a randomized crossover study to receive 30 g ethanol/d as cava or gin for 28 d. Before both interventions, subjects abstained from alcohol for 2 wk. Inflammatory biomarkers of atherosclerosis and expression of adhesion molecules on peripheral leukocytes were measured before and after each intervention. Likewise, dietary intake and exercise were also evaluated. Expression of lymphocyte function-associated antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), Sialyl-Lewis(x) (SLe(x)), and CD40 on monocytes decreased after cava intake (all P < 0.05), whereas only SLe(x) was reduced after gin intake (P = 0.036). Circulating markers of atherosclerosis including vascular cell adhesion molecule-1, E-selectin, and P-selectin decreased after both interventions (all P < 0.05). High-sensitivity C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), IL-6, monocyte chemoattractant protein-1 (MCP-1), and CD40L were diminished only after cava intake (all P < 0.05). The effects of cava on circulating CD40L, ICAM-1, and MCP-1, and monocyte surface expression of CD40, LFA-1, and VLA-4 were greater than those of gin (all P < 0.05). In conclusion, both cava and gin showed antiinflammatory properties; however, cava had a greater protective effect, probably due its polyphenol content.
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PMID:Inflammatory markers of atherosclerosis are decreased after moderate consumption of cava (sparkling wine) in men with low cardiovascular risk. 1788 11


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