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)

Interruption of inflammatory pathways may provide a novel approach to the therapy of atherosclerosis. Recently, we and others have implicated the immune mediator dyad CD40/CD40L (CD40 ligand), which is expressed on endothelial and smooth muscle cells, macrophages, and T lymphocytes within human atherosclerotic lesions, in aspects of atherogenesis and the acute coronary syndromes, including regulation of matrix metalloproteinases, procoagulant activity, cytokines, etc. In vivo, interruption of CD40 signaling reduced the initiation and early phases of atheroma formation in hypercholesterolemic mice. However, whether interruption of CD40 signaling can retard the progression or even regress established lesions remains unknown. We report here that anti-CD40L antibody treatment of randomly assigned low-density lipoprotein receptor-deficient mice during the second half of a 26-week regimen of high-cholesterol diet did not regress, but did significantly reduce further evolution of established atherosclerotic lesions within the aortic arch and particularly the thoracic and abdominal aorta, as compared with control treatment (application of rat-IgG or saline; 13 weeks, continued high-cholesterol diet). In addition to limiting lesion progression, anti-CD40L treatment changed the composition of atheroma in manners thought to favor plaque stability, e.g., reduced relative content of macrophages and lipid, as well as increased relative content of smooth muscle cells and collagen. These data implicate CD40/CD40L as crucial mediators not only in the initial events of atherogenesis but also during the evolution of established atheroma. This study lends further support to the importance of this specific inflammatory signaling pathway in atherosclerosis and its complications.
 ...
PMID:Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. 1086 Sep 49

In the present study, we investigated the role of the CD40L-CD40 pathway in a model of progressive atherosclerosis. ApoE-/- mice were treated with an anti-CD40L antibody or a control antibody for 12 wk. Antibody treatment started early (age 5 wk) or was delayed until after the establishment of atherosclerosis (age 17 wk). In both the early and delayed treatment groups, anti-CD40L antibody did not decrease plaque area or inhibit lesion initiation or age-related increase in lesion area. The morphology of initial lesions was not affected, except for a decrease in T-lymphocyte content. Effects of anti-CD40L antibody treatment on the morphology of advanced lesions were pronounced. In both the early and delayed treatment groups, T-lymphocyte content was significantly decreased. Furthermore, a pronounced increase in collagen content, vascular smooth muscle cell/myofibroblast content, and fibrous cap thickness was observed. In the delayed treatment group, a decrease in lipid core and macrophage content occurred. Interestingly, advanced lesions of anti-CD40L antibody-treated mice exhibited an increased transforming growth factor beta1 immunoreactivity, especially in macrophages. In conclusion, both early and delayed treatment with an anti-CD40L antibody do not affect atherosclerotic lesion initiation but do result in the development of a lipid-poor collagen-rich stable plaque phenotype. Furthermore, delayed treatment with anti-CD40L antibody can transform the lesion profile from a lipid-rich to a lipid-poor collagen-rich phenotype. Postulated mechanisms of this effect on plaque phenotype are the down-regulation of proinflammatory pathways and up-regulation of collagen-promoting factors like transforming growth factor beta.
 ...
PMID:Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. 1086 Sep 49

T cells have roles in the pathogenesis of native coronary atherosclerosis (CA) and transplant-associated coronary artery disease (TCAD). The mechanisms by which T cells interact with other cells in these lesions are not fully known. CD154 is an activation-induced CD4+ T cell surface molecule that interacts with CD40+ target cells, including macrophages and endothelial cells, and induces the production of pro-inflammatory molecules, including CD54 (ICAM-1) and CD106 (VCAM-1). To investigate whether CD154-CD40 interactions might be involved in the pathogenesis of CA or TCAD we performed immunohistochemical studies of CD154 and CD40 expression on frozen sections of coronary arteries obtained from cardiac allograft recipients with CA (n=10) or TCAD (n=9). Utilizing four different anti-CD154 mAb we found that CD154 expression was restricted to infiltrating lymphocytes in CA and TCAD. CD40 expression was markedly up-regulated on intimal endothelial cells, foam cells, macrophages and smooth muscle cells in both diseases. Dual immunolabeling demonstrated many CD40+ cells co-expressed CD54 and CD106. The extent of CD40, CD54 and CD106 expression showed statistical significant correlation with the severity of disease and the amount of intimal lymphocytes. Together these studies demonstrate the presence of activated CD154+ and CD40+ cells in both CA and TCAD lesions and suggest that CD154-mediated interactions with CD40+ macrophages, foam cells, smooth muscle cells and/or endothelial cells may contribute to the pathogenesis of these diseases.
 ...
PMID:Analysis of CD154 and CD40 expression in native coronary atherosclerosis and transplant associated coronary artery disease. 1099 75

CD40-CD40L receptor-ligand interaction plays a central role in antigen presentation, immunological reactions, and in T-cell and macrophage activation. Since all these mechanisms are important for the pathogenesis of atherosclerosis, we studied the expression profile of CD40-CD40L in different types of human atherosclerotic lesions using double immunostaining techniques with cell type-specific antibodies. Normal human intima did not contain CD40 or CD40L immunoreactivity. From type-II lesions (fatty streaks) to advanced type-VI lesions (complicated plaques), colocalization of CD40 and CD40L was observed in T cells (CD3+ cells), macrophages (CD68+ cells), and smooth muscle cells (HHF35+ cells). No correlation was found between the lesion type and CD40-CD40L expression. Positive lesions had dense infiltrations of macrophages and macrophage-derived foam cells together with T cells. The most intensive immunoreactivity for the CD40 receptor and its ligand CD40L was found in macrophage- and T-cell-rich pockets, where both cell types were in close contact with each other. The majority of macrophages, and especially those of macrophage-derived foam cells, were positive for both CD40 and CD40L. A small subset of the lesion macrophage population (10-20%) consisted of cells positive only for either CD40 or CD40L, suggesting the presence of a subpopulation of macrophages more active in inflammatory processes than in lipid uptake. Intimal smooth muscle cells in and around the macrophage-rich areas as well as some of the medial smooth muscle cells near the lesions stained positive for CD40 and CD40L. Moderate to faint expression of these proteins was also found in endothelium. In addition, CD40-CD40L immunoreactivity colocalized with epitopes characteristic of oxidized low-density lipoprotein, scavenger receptor class A, and CD16 (Fc gammaRIII), thus suggesting the involvement of CD40-CD40L and these pathogenetic mediators in foam cell formation, progression of atherosclerotic lesions, and differentiation of immunologically active subsets of macrophages. These results support the hypothesis that CD40-CD40L interaction is involved in atherogenesis and that it might provide a target for future therapeutic interventions.
 ...
PMID:Macrophages, smooth muscle cells, endothelial cells, and T-cells express CD40 and CD40L in fatty streaks and more advanced human atherosclerotic lesions. Colocalization with epitopes of oxidized low-density lipoprotein, scavenger receptor, and CD16 (Fc gammaRIII). 1109 65

Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines, matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory processes and prevalent human diseases.
 ...
PMID:The CD40/CD154 receptor/ligand dyad. 1122 15

Immune-mediator CD40 ligand is expressed on a variety of cell types involved in the immune response and on the cells of the vascular system. Inhibition of CD40 signaling has been associated with reduction of experimental atherosclerosis and transplant-associated vasculopathy. Immune response also plays a cardinal role in intimal thickening after acute arterial-wall injury. After carotid artery injury in CD40 ligand knockout (CD40L(-/-)) mice, the intimal thickening was increased 3-fold compared with the thickening in background B6/129 mice. The extent of thickening was similar to the thickening in B6/129 mice depleted of T lymphocytes with anti-CD4 and anti-CD8 antibodies. Injection of splenocytes from B6/129 mice into the CD40L(-/-) mice reduced the intimal thickening to the level comparable to the thickening in background B6/129 mice. These data suggest that CD40 signaling plays a significant role in the inhibitory effect of T lymphocytes on intimal thickening after arterial injury.
 ...
PMID:Absence of CD40 signaling is associated with an increase in intimal thickening after arterial injury. 1123 Jan 5

Despite numerous basic and applied studies into the pathogenesis and treatment of atherosclerosis, there is no theory which could explain the development of the whole complex of changes united under the term "atherosclerosis". Examining the causes of atherosclerosis disclosed a pathogenetic association of the immunoregulatory signal CD40-CD40L with the occurrence of arterial atherosclerotic lesions. Studies of the immune mechanisms responsible for the pathogenesis of atherosclerosis (autoimmune complexes containing oxidative modification of LDL, T and B lymphocytes, inflammation mediators, hemoadhesive molecules, and immunoregulatory molecules showed the leading role of autoimmune mechanisms in atherosclerosis. The conceptual result of the studies is that the authors have elucidated the leading role of immune inflammation in the appearance and development of arterial atherosclerotic lesions. The development of a new concept of assessing the pathogenesis of atherosclerosis in the context of immune inflammation in the vascular wall opens new vistas for the treatment of this disease.
 ...
PMID:[Atherogenesis as a reflection of immune inflammation in the vascular wall]. 1124 26

Atherosclerosis is a leading cause of cardiovascular disease in the westernized world. This review highlights emerging evidence linking atherosclerosis to the CD40-CD40 ligand (CD154) pathway. Recently, atherosclerosis has been associated with chronic inflammation, linking it to the immune system. This novel viewpoint may serve as an additional target for therapeutic intervention. CD40 and CD154 are highly expressed in atherosclerotic human plaques. Recent data from preclinical animal models of atherosclerosis show that disruption of the CD40-CD154 pathway can prevent atherosclerotic progression and may reverse established lesions. Blockade of the CD40-CD154 pathway by biologicals or small molecules may prove valuable in the treatment of atherosclerosis.
 ...
PMID:The CD40-CD40 ligand system: a potential therapeutic target in atherosclerosis. 1157 55

Interstitial collagen constitutes the predominant structural component of the fibrous cap of atherosclerotic plaque. The balance between synthesis and degradation of this extracellular matrix protein probably determines plaque stability and hence the tendency for plaque rupture. The CD40/CD40L signaling dyad has been implicated as an important regulatory pathway of collagen-degrading activity in atherosclerosis via the induction of matrix metalloproteinases (MMPs). However, the role of CD40 signaling in the synthesis of interstitial collagen and thus in the overall rate of collagen turnover has remained unknown. We demonstrate here that CD40 ligation on cultured human vascular smooth muscle cells (SMCs) diminishes the detectable content of de novo synthesized interstitial procollagens. Notably, the loss of collagen is not accompanied by a reduction in collagen transcript expression but can be prevented by MMP inhibition. These data demonstrate that CD40 signaling in human vascular SMC shifts interstitial collagen turnover towards the loss of this extracellular matrix protein by accelerating its degradation without concomitantly diminishing its synthesis. Thus, CD40/CD40L interactions might play a key role in rendering atheromatous lesions prone to rupture.
 ...
PMID:Ligation of CD40 onvascular smooth muscle cells mediates loss of interstitial collagen via matrix metalloproteinase activity. 1179 84

Increasing evidence supports a central role for CD40-CD40L interactions in the pathogenesis of atherosclerosis. Recently, we have shown that CD40L deficiency as well as pharmacological inhibition of CD40L in ApoE(-/-) mice results in the development of a stable atherosclerotic plaque phenotype. This phenotype is rich in smooth muscle cells and collagen, and contains only a small amount of macrophages and T-lymphocytes. CD40 and CD40L protein are present in almost all cell types in human atherosclerotic lesions. Expression was observed in early plaques, but was more predominant in advanced, rupture-prone, and ruptured plaques. Because most of the acute complications of atherosclerosis are the result of plaque rupture, CD40L inhibition might be a novel therapeutic approach to prevent atherosclerotic plaque destabilization and plaque rupture.
 ...
PMID:CD40-CD40L interactions in atherosclerosis. 1179 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>