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)

Apolipoprotein A-I (apoA-I), the major protein component of serum high-density lipoprotein, exhibits anti-inflammatory activity in atherosclerosis. In this study, we demonstrate that apoA-I inhibits DC differentiation and maturation. DC differentiated from monocytes in the presence of apoA-I showed a decreased expression of surface molecules such as CD1a, CD80, CD86, and HLA-DR. In addition, these DC exhibited decreased endocytic activity and weakened allogeneic T-cell activation. During DC differentiation in the presence of apoA-I, PGE(2) and IL-10, which are known to be DC differentiation inhibitors and/or modulators of DC function, were produced at remarkable rates, whereas IL-12 production in the cells after stimulation with CD40 mAb and IFN-gamma was significantly decreased in comparison with the control DC. T cells stimulated by apoA-I-pretreated DC produced significantly low levels of IFN-gamma, and apoA-I inhibited cross-talk between DC and NK cells, in terms of IL-12 and IFN-gamma production. Therefore, apoA-I appears to play an important role in modulating both innate immune response and inflammatory response. The novel inhibitory function of apoA-I on DC differentiation and function may facilitate the development of new therapeutic interventions in inflammatory diseases.
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PMID:Apolipoprotein A-I induces IL-10 and PGE2 production in human monocytes and inhibits dendritic cell differentiation and maturation. 1625 56

This study investigated the expression of CD40, CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) in dietary-induced atherosclerosis in rats. Wister rats were fed with high cholesterol diet (As group, n = 6) or with normal diet (N group, n = 6). Blood cells that express CD40 and CD40L were sorted by flow cytometry, the MMP-2 and MMP-9 were measured by zymography method. The morphological locations of MMP-2 and MMP-9 in the aorta were studied with immunohistochemistry and by microscopy. The results showed that the expression of CD40, CD40L and matrix metalloproteinase were higher in As group than those in control group. The MMP-2 and MMP-9 were positive in As group but negative in control group by immunohistochemistry study. Our results suggest that the expression of CD40 and CD40L in the blood cells and the activities of MMP-2 and MMP-9 in plasma were higher in As group than those in Normal group, indicating that they may contribute to the formation of atherosclerosis.
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PMID:The expression of CD40-CD40L and activities of matrix metalloproteinases in atherosclerotic rats. 1631 21

CD40 is a 48kDa phosphorylated transmembrane glycoprotein that belongs to the tumor necrosis factor receptor superfamily and may play a role in formation of atherosclerotic plaques. Here, we investigated the effect of chylomicron remnants on CD40 expression in the human premonocytic cell line, THP-1 cells. Chylomicron remnants upregulated the expression of CD40 protein and mRNA in a dose- and time-dependent manner. Further, chylomicron remnants increased the generation of reactive oxygen species as determined by an increasing level of 2',7'-dichlorofluorescein. Pretreatment with the antioxidant, N-acetylcysteine, inhibited chylomicron remnant-induced CD40 protein expression by 60%. On the other hand, chylomicron remnants transiently increased the phosphorylation of extracellular signal-regulated kinase (ERK 1/2) and p38 mitogen-activated protein kinase (MAPK). Pretreatment with the MAPK kinase inhibitor, U0126, completely inhibited chylomicron remnants-induced CD40 protein expression, whereas the p38 MAPK inhibitor, SB203580, had no effect. Pretreatment with N-acetylcysteine had no effect on chylomicron remnant-induced ERK 1/2 phosphorylation. These data suggest that CD40 expression stimulated by chylomicron remnants in THP-1 cells is dependent on ERK 1/2-mediated pathway, which is followed by redox-sensitive mechanism-dependent and independent pathway. Thus, chylomicron remnants may contribute to the formation of atherosclerotic plaques via their immunological and proinflammatory effects.
Atherosclerosis 2006 Aug
PMID:Chylomicron remnants upregulate CD40 expression via the ERK pathway and a redox-sensitive mechanism in THP-1 cells. 1635 5

IL-12 drives type I immune responses and can mediate chronic inflammation that leads to host defense as well as disease. Recently, we discovered a novel role for 12/15-lipoxygenase (12/15-LO) in mediating IL-12p40 expression in atherosclerotic plaque and in isolated macrophages. We now demonstrate that 12/15-LO regulates IL-12 family cytokine production in a cell-type and stimulus-restricted fashion. LPS-stimulated elicited peritoneal macrophages derived from 12/15-LO-deficient (Alox15) mice produced reduced IL-12 and IL-23 levels, but comparable amounts of several other inflammatory mediators tested. Furthermore, LPS stimulation triggered an increase in wild-type macrophage 12/15-LO activity, whereas pharmacological inhibition of 12/15-LO activity suppressed LPS-induced IL-12 production in wild-type macrophages. 12/15-LO-deficient macrophages also produced reduced levels of IL-12 in response to TLR2 stimulation, but not in response to CpG (TLR9) or CD40/CD40L-mediated activation. In contrast to our previous finding of reduced IL-12 production in the setting of atherosclerosis, we found that comparable IL-12 levels were produced in Alox15 and wild-type mice during an acute response to LPS in vivo. This paradox may be explained by normal production of IL-12 by 12/15-LO-deficient neutrophils and dendritic cells, which are major sources of IL-12 during acute inflammation. Finally, we detected selectively decreased association of the transcription factors IFN consensus sequence binding protein and NF-kappaB with the IL-12p40 promoter in 12/15-LO-deficient macrophages. Taken together, these findings reveal a highly selective pathway to IL-12 production that may prove a useful target in chronic inflammation while sparing the acute response to infection.
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PMID:Cellular and molecular mechanisms of the selective regulation of IL-12 production by 12/15-lipoxygenase. 1636 18

Advanced glycation end products (AGEs), the senescent macroprotein derivatives that form in increased amounts in diabetes, have been implicated in the pathogenesis of accelerated atherosclerosis. There is a growing body of evidence that CD40-CD40 ligand (CD40L) interaction also plays an important role in atherogenesis. However, the effects of AGEs on CD40-CD40L signaling in endothelial cells (ECs) remain to be elucidated. In this study, we investigated (i) whether injection of AGE-proteins to normal rats stimulates CD40L expression on circulating platelets and (ii) whether AGEs up-regulate CD40 mRNA levels in cultured ECs. We further examined the effects of nifedipine, one of the most popular dihydropyridine-based calcium antagonists, on CD40 gene expression in AGE-exposed ECs. Platelet surface CD40L expression was increased in AGE-bovine serum albumin (AGE-BSA)-injected rats, compared with nonglycated BSA administration. AGEs were found to induce up-regulation of CD40 mRNA levels in ECs, which were significantly blocked by nifedipine. These results suggest that AGEs could enhance CD40-CD40L interaction, thereby promoting atherosclerosis in diabetes. Blockade of CD40-CD40L signaling in ECs may be a molecular target for the vasculoprotective property of nifedipine.
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PMID:Blockade by nifedipine of advanced glycation end product-induced CD40-CD40 ligand interaction in endothelial cells. 1642 79

Mounting evidence from a growing body of epidemiologic studies demonstrates that patients with systemic lupus erythematosus (SLE) are at increased risk for the development of premature cardiovascular disease (CVD). However, awareness of accelerated atherosclerosis in young SLE patients, albeit growing, is still limited, as documented by the brief case presented. Inflammation is thought to play an important role in both the pathogenesis of SLE, as well as atherosclerotic vascular disease. Inflammatory processes that are shared by SLE and atherosclerotic disease include immune complex deposition and fixation, autoantibody binding, complement activation and CD40-CD40 ligand interaction. By examining the inflammatory mechanisms in common between SLE and atherosclerotic disease, we can come to a better understanding of the pathophysiology of the accelerated atherosclerotic process seen in patients with SLE and can gain insights into developing and instituting preventative and treatment strategies. In this article, we present a case of a young woman with SLE who presents with chest pain, followed by a review of inflammation-based pathogenic mechanisms that are shared by SLE and atherosclerotic cardiovascular disease.
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PMID:Premature atherosclerotic disease in systemic lupus erythematosus--role of inflammatory mechanisms. 1643 36

CD40-CD40 ligand interaction is involved in the inflammatory pathogenesis of atherosclerosis but clinical data about its role in stent restenosis are still limited. We investigated the effect of preprocedural CD40 ligand (sCD40L) on stent restenosis. We enrolled 36 patients (mean age 61.4 +/- 8.5 years) with stable angina who underwent successful stent implantation. Control angiograms were performed in all patients after 6 months. Plasma sCD40L and high-sensitive C-reactive protein levels were measured before stent implantation and at 1 and 6 months after the procedure. Angiographically proven restenosis rate was 27.8%. Plasma sCD40L levels were significantly higher (preprocedural 0.74 +/- 0.79) and more prolonged in patients with stent restenosis compared with patients without stent restenosis (0.02 +/- 0.22 ng/ml, p < 0.001). According to receiver-operator characteristic analysis, sCD40L > 0.41 ng/ml was the best distinguished parameter between patients with and without restenosis. At the multivariate logistic regression analysis, preprocedural sCD40L was an independent predictor (RR 39.4, 95% confidence interval 4.05 to 383.8, p = 0.002) of stent restenosis after adjusting for confounding variables, including diabetes, reference vessel diameter, lesion length, stent diameter, stent length, and baseline high-sensitive C-reactive protein. Sensitivity, specificity, and positive and negative predictive values and likelihood ratio of preprocedural sCD40L levels in stent restenosis were 78%, 92%, 78%, 92%, and 9.37%, respectively. In conclusion, enhanced inflammation of plaque (increased sCD40L) before percutaneous coronary intervention may increase the rate of stent restenosis. Increased preprocedural sCD40L level is an independent predictor of stent restenosis. We can use this marker for the assessment of risk stratification before planning stent implantation.
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PMID:Usefulness of preprocedural soluble CD40 ligand for predicting restenosis after percutaneous coronary intervention in patients with stable coronary artery disease. 1644 63

Atherosclerosis (AT) is a chronic autoimmune inflammatory disease, characterized by lipoproteins metabolism alteration leading to formation of pro-inflammatory and pro-oxidative lipids and immune response. Identification of macrophages, T cells, pro-inflammatory cytokines, adhesion cell molecules in atherosclerotic lesions support the hypothesis that innate and adaptive immune response participate in the atherogenesis mechanism. Multiple factors such as inflammatory, infectious and immune system, among others participate in this process. The principal antigens identified in atherogenesis are: oxidized LDL (oxLDL), HSPs and beta2GPI. During LDL oxidation, multiple neoantigens are formed (anti-EO). These antibodies seem to be protective. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have accelerated AT. The association of both diseases with AT suggests a common pathogenic mechanism. SLE and atherosclerosis are immune-complex mediated diseases. Participation of complement activation, and CD40, CD40 ligand interactions have been demonstrated in AT and SLE. AT may be the initial presentation or the consequence of primary antiphospholipid syndrome. The similarities between AT, SLE, and APS and the identification of protective antibodies offer opportunities for new immunomodulation treatment strategies.
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PMID:Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases. 1648 19

The high incidence of cardiovascular complications in patients with chronic renal failure (CRF) is partly explained by more aggressive atherosclerosis, i.e. increased incidence and severity of lesions with higher tendency to calcification. The pathogenesis of this accelerated atherosclerosis, however, is not completely understood. Among other risk factors, chronic micro-inflammation may be involved. Activation of cells and adhesion molecules in atherosclerosis is governed by CD40-CD154 (CD40 ligand) interaction. Therefore, we investigated the expression and distribution of CD40-CD154 in different coronary atherosclerotic lesions of CRF patients and non-renal control patients. Coronary plaques of 57 patients with and without CRF were categorized according to the Stary classification and analysed for in situ protein expression of CD40, CD154 and CRP using immunohistochemistry and a semiquantitative scoring system. The nature, number and distribution of infiltrating cells was analysed and correlated to the types of coronary lesions and in particular to the presence of calcification. CD40 was over expressed in media myocytes of coronary plaques of both uremic and control patients. Inside the plaques, CD40 was expressed on endothelial cells, T lymphocytes, macrophages, fibroblasts, and smooth muscle cells. CD154 expression was seen on T cells in areas densely infiltrated by CD40 positive macrophages. In uremic and control patients higher in situ expression of CD40, CD154 and CRP was seen in calcified compared to non-calcified lesions. Inside the plaques, there were significant differences in the expression pattern of CD40 and CD154 between uremic and control patients. In addition, in uremic patients coronary plaques showed higher CRP protein expression compared to control patients. The data indicate a higher inflammatory status of coronary lesions as well as involvement of the CD40-CD154 signaling cascade in CRF patients, especially in cases of calcified atherosclerotic lesions.
Atherosclerosis 2007 Jan
PMID:CD40-CD154 expression in calcified and non-calcified coronary lesions of patients with chronic renal failure. 1649 85

The endothelium is of important significance in the development of the acute coronary syndrome. As an endo-/paracrine organ, the endothelium plays a key role in the regulation of the vascular homeostasis. The endothelial integrity and above all the bioavailability of nitric oxide (NO) are essential for the correct function of the endothelium. Cardiac risk factors may lead to an endothelial dysfunction with a consecutive imbalance of the vascular homeostasis. In an inflammatory or prothrombotic state the endothelium shows a number of abnormalities such as oxidative stress, expression of cell adhesion molecules, activation of cell signal-systems (renin-angiotensin-system, CD40/CD40L-system) and especially the loss of NO. The inflammatory cascades lead to coronary atherosclerosis over years or, more instantly, to the acute coronary syndrome caused by endothelial erosion or the rupture of an instable plaque. The knowledge of the pathophysiological processes in the arterial wall during the acute coronary syndrome may lead to the identification of high risk patients and the development of more targeted therapies.
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PMID:[Role of the vascular wall in the pathophysiology of the acute coronary syndrome]. 1667 55


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