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)

Although soluble CD40L (sCD40L, possibly derived from platelets and pro-inflammatory in vitro) may be implicated in thrombosis and haemostasis, there are little data in peripheral artery disease (PAD). We hypothesised the following: (a) that sCD40L relates to the clinical severity of PAD; and (b) that peripheral artery angioplasty acutely raises sCD40L levels. sCD40L was compared to established platelet markers soluble P selectin, platelet microparticles and platelet surface expression of CD62 and CD63. We recruited 36 healthy controls, 33 patients with intermittent claudication (IC), and 33 with symptomatically more severe critical limb ischaemia (CLI), measuring plasma markers by ELISA and membrane markers by flow cytometry. Eleven patients with CLI subsequently underwent peripheral artery angioplasty: blood was taken before and 10 minutes after the intervention. Results show that sCD40L was raised in IC at median 68 (IQR 28-333) pg/ml and in CLI at 64 (34-282) pg/mL compared to 35 (IQR 28-55) pg/ml in the healthy controls (p=0.009). Levels were no different between IC and CLI. The same distribution pattern was present for soluble P selectin, %platelets CD62+ve and CD63+ve. sCD40L failed to correlate significantly with ABPI (p=0.264), unlike %platelets CD62+ve (p=0.0032) and CD63+ve (p=0.009). Pre-angioplasty sCD40L level of 72 (35-610) ng/ml rose to 100 ng/ml (IQR=60-237)(p=0.018) post-angioplasty. Plasma sCD40L, in addition to other platelet indices, is raised in peripheral atherosclerosis and is increased by peripheral artery angioplasty, although levels seem unrelated to clinical severity. Failure to correlate with other markers suggest the platelet may not be the sole source of sCD40L, and that other cells may contribute to plasma levels.
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PMID:Soluble CD40L in peripheral artery disease. Relationship with disease severity, platelet markers and the effects of angioplasty. 1573 13

Atherosclerosis is an inflammatory response of the arterial wall to "injury", which is prominently driven by cytokines. The inflammatory mediator macrophage migration inhibitory factor (MIF) is a unique cytokine that was recently associated with atherogenesis. Here, we have investigated whether MIF has a role in spontaneous atherosclerosis by studying apolipoprotein E-deficient (ApoE(-/-)) mice treated with neutralizing anti-MIF monoclonal antibody and comparison with isotype IgG-treated controls. After 14 weeks, the aortas and heart valves were analyzed for inflammatory status, macrophage content and plaque areas. MIF expression in the aortic wall was elevated upon spontaneous atherogenesis, with foam cells representing a major source. Of note, MIF blockade led to a marked reduction in intimal Mac-1-positive macrophages. Similarly, treatment with anti-MIF antibody led to a reduction of a variety of inflammatory mediators typically associated with atherosclerosis including the circulating levels of fibrinogen, MIF and IL-6. Importantly, the local aortic expression of ICAM-1, MMP-2, TNF, IL-12, and CD40L was reduced by MIF blockade, as were the levels of the phospho-c-Jun and C/EBPbeta transcription factors. The observed strong reduction of inflammatory parameters by anti-MIF treatment was associated with a small, yet non-significant, reduction in aortic plaque area. Thus, although MIF's role is not directly linked to plaque volume expansion, in this mouse model of spontaneous atherogenesis, MIF plays an important role in intimal inflammation.
Atherosclerosis 2006 Jan
PMID:Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF). 1592 87

The presence of activated platelets and platelet-leukocyte aggregates in the circulation accompanies major surgical procedures and occurs in several chronic diseases. Recent findings that activated platelets contribute to the inflammatory disease atherosclerosis made us address the question whether activated platelets stimulate normal healthy endothelium. Infusion of activated platelets into young mice led to the formation of transient platelet-leukocyte aggregates and resulted in a several-fold systemic increase in leukocyte rolling 2 to 4 hours after infusion. Rolling returned to baseline levels 7 hours after infusion. Infusion of activated P-selectin-/- platelets did not induce leukocyte rolling, indicating that platelet P-selectin was involved in the endothelial activation. The endothelial activation did not require platelet CD40L. Leukocyte rolling was mediated solely by the interaction of endothelial P-selectin and leukocyte P-selectin glycoprotein ligand 1 (PSGL-1). Endothelial P-selectin is stored with von Willebrand factor (VWF) in Weibel-Palade bodies. The release of Weibel-Palade bodies on infusion of activated platelets was indicated by both elevation of plasma VWF levels and by an increase in the in vivo staining of endothelial P-selectin. We conclude that the presence of activated platelets in circulation promotes acute inflammation by stimulating secretion of Weibel-Palade bodies and P-selectin-mediated leukocyte rolling.
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PMID:Activated platelets induce Weibel-Palade-body secretion and leukocyte rolling in vivo: role of P-selectin. 1595 87

Inhibition of CD40-CD40L interactions results in a reduction of innate regulatory T cells (Tregs) in CD40(-/-) mice and induces a stable plaque phenotype in atherosclerosis-prone mouse strains. Here we investigated the effects of leukocyte CD40L on the Treg population and on atherosclerosis. LDLR(-/-) mice were reconstituted with wild-type or CD40L(-/-) bone marrow (BM). These BM chimeras were analysed by flow cytometry for the presence of innate Tregs (CD45RB(low) CD25(+) CD4) in lymphoid organs and peripheral blood. As in CD40(-/-) mice, the CD45RB(high):CD45RB(low) CD4 T cell ratio significantly increased and the CD25(+) CD4(+) subpopulation significantly decreased in LDLR(-/-) mice receiving CD40L(-/-) BM compared to LDLR(-/-) mice receiving wild-type BM. However, atherosclerotic plaque progression and plaque phenotype did not change in LDLR(-/-) mice reconstituted with CD40L(-/-) BM. In conclusion, the present study shows that CD40-CD40L interactions on leukocytes are essential for the size of the CD45RB(low) CD25(+) CD4 Treg subpopulation. Nevertheless, CD40L deficiency on hemopoietic cells did not affect atherosclerosis, implying that CD40L expressing leukocytes alone are not responsible for the stable plaque phenotype observed after total CD40L blockade.
Atherosclerosis 2005 Dec
PMID:Leukocyte CD40L deficiency affects the CD25(+) CD4 T cell population but does not affect atherosclerosis. 1600 76

Atherosclerosis, and the resulting coronary heart disease and stroke, is the most common cause of death in developed countries. Atherosclerosis is an inflammatory process that results in the development of complex lesions or plaques that protrude into the arterial lumen. Plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction (MI) and stroke. Although certain risk factors (dyslipidemias, diabetes, hypertension) and humoral markers of plaque vulnerability (C-reactive protein, interleukin-6, 10 and 18, CD40L) have been identified, a highly sensitive and specific biomarker or protein profile, which could provide information on the stability/vulnerability of atherosclerotic lesions, remains to be identified. In this review, we report several proteomic approaches which have been applied to circulating or resident cells, atherosclerotic plaques or plasma, in the search for new proteins that could be used as cardiovascular biomarkers. First, an example using a differential proteomic approach (2-DE and MS) comparing the secretome from control mammary arteries and atherosclerotic plaques is displayed. Among the different proteins identified, we showed that low levels of HSP-27 could be a potential marker of atherosclerosis. Second, we have revised several studies performed in cells involved in the pathogenesis of atherosclerosis (foam cells and smooth muscle cells). Another approach consists of performing proteomic analysis on circulating cells or plasma, which will provide a global view of the whole body response to atherosclerotic aggression. Circulating cells can bear information reflecting directly an inflammatory or pro-coagulant state related to the pathology. As an illustration, we report that circulating monocytes and plasma in patients with acute coronary syndromes has disclosed that mature Cathepsin D is increased both in the plasma and monocytes of these patients. Finally, the problems of applying proteomic approach directly to plasma will be discussed. The purpose of this review is to provide the reader with an overview of different proteomic approaches that can be used to identify new biomarkers in vascular diseases.
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PMID:Quest for novel cardiovascular biomarkers by proteomic analysis. 1608 68

Elevated soluble CD40 ligand (sCD40L) levels are associated with an increased risk of cardiovascular events in patients with acute coronary syndromes and in middle-aged healthy women. However, the relationship between sCD40L and global risk assessment remains unclear. The present study was designed to examine the relationship between sCD40L and Framingham Coronary Heart Disease Risk Scores (FCRS) in healthy middle-aged men. The study population consisted of 400 active and retired male firefighters, with no previous history of cardiovascular disease, as part of the Firefighters and Their Endothelium (FATE) study. FCRS correlated poorly with sCD40L levels (p=0.14). Soluble CD40L concentrations correlated only with total (r=0.105; p=0.035) and LDL cholesterol (r=0.104; p=0.039), and CRP levels (r=0.11; p=0.03). Compared with participants with sCD40L levels <4.36 ng/mL (75th percentile), participants with sCD40L levels >4.36 ng/mL had higher total (p=0.016) and LDL cholesterol (p=0.018), CRP levels (p=0.034) and FCRS (p=0.012). Multivariate analysis revealed that CRP level was the only parameter that independently correlated with the sCD40L levels (p=0.032). This is the first study to evaluate the relationship between sCD40L levels and Framingham global risk assessment in a large cohort of otherwise healthy individuals. We demonstrate that sCD40L levels poorly correlate with both the individual components and the calculated FCRS. Long-term follow-up of the FATE study will shed light on whether the predictive value of sCD40L is independent of Framingham based global risk assessment.
Atherosclerosis 2005 Oct
PMID:The relationship between soluble CD40 ligand levels and Framingham coronary heart disease risk score in healthy volunteers. 1615 9

Cell adhesion and proteolytic matrix degradation are central processes in atherosclerosis. Being a member of the family of ADAMs ("a disintegrin and metalloproteinase"), metargidin (ADAM15) combines a metalloproteinase domain and an RGD aminoacid sequence. We studied the potential role of ADAM15 as an adhesion receptor on endothelial cells and interactions between platelets and ADAM15 with respect to platelet adhesion, activation and thrombus formation. ADAM15 was found to be expressed on cultured endothelial cells (HUVEC). Platelet adhesion to immobilized recombinant ADAM15 was effectively enhanced under both static and high shear rate conditions reaching the maximum level of adhesion to fibrinogen. Consistently, platelet adhesion onto ADAM15 overexpressing endothelial cells was significantly increased. Adhesion to ADAM15 was reduced by blockade of GPIIb-IIIa using neutralizing anti-alpha(IIb)beta3 mAbs (7E3, 2G12), but not by anti-alpha(v)beta3 (LM609). Soluble ADAM15 binds to activated but not to resting GPIIb-IIIa. Moreover, platelets adherent to ADAM15 additionally attracted platelets under high shear rates indicating an initial role of platelet-ADAM15 interactions for thrombus formation. Furthermore, incubation of platelets with soluble ADAM15 showed a dose-dependent increase in secretion of CD62P and CD40L. ADAM15 is expressed on endothelial cells and can serve as an adhesion receptor for platelets via GPIIb-IIIa binding. Platelet adhesion to ADAM15 leads to platelet activation, secretion and promotes thrombus formation. Thus, ADAM15 may represent a novel target for antithrombotic strategies in cardiovascular pathologies.
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PMID:ADAM 15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation. 1626 72

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

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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