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)

Inflammation contributes to a variety of arterial diseases including atherosclerosis. Interleukin 1beta (IL-1beta) in its activated mature 17-kDa form may mediate aspects of vascular inflammation. As shown previously, human vascular wall cells, such as smooth muscle cells (SMC), express the IL-1beta precursor upon stimulation and the IL-1beta-converting enzyme (ICE) constitutively but do not produce mature IL-1beta or express ICE activity. How SMC, the most numerous cell type in arteries, may release active IL-1beta has therefore remained a perplexing problem. We report here that stimulation of human vascular SMC and endothelial cells (EC) through CD40 ligand, a mediator recently localized in human atheroma, induced elaboration of the IL-1beta precursor as well as activation of cell-associated ICE. In addition to the constitutively expressed 45- and 30-kDa immunoreactive ICE proteins, vascular cells incubated with recombinant human CD40 ligand (rCD40L) (but not IL-1 or TNF) showed an increase of a 20-kDa immunoreactive ICE protein by Western blot analysis. Furthermore, SMC and EC stimulated through rCD40L processed recombinant human IL-1beta precursor (pIL-1beta), generating a cleavage product of approximately 17 kDa. Appearance of both the 20-kDa immunoreactive ICE protein and pIL-1beta processing activity required at least 6 h of stimulation with 0.3 or 1.0 microg/ml rCD40L, respectively, and was inhibited by pre-incubation of the ligand with an anti-CD40L antibody. Stimulation of vascular SMC and EC through rCD40L resulted in the release of biologically active IL-1beta, indicating processing of the native IL-1beta precursor induced by the ligand. These findings establish a novel mechanism of IL-1beta activation in human vascular cells and, moreover, indicate a new pathway of ICE-activation, which could participate in inflammatory aspects of atherogenesis and other disease states.
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PMID:Ligation of CD40 activates interleukin 1beta-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1beta. 923 62

Atherosclerosis is one of the most prevalent fatal diseases in Western societies, and results from an intricate interplay between diverse factors such as lipid metabolism, blood coagulation elements, cytokines, hemodynamic stress, and behavioral risk factors. Atherosclerotic lesions are characterized by the infiltration of immune competent cells such as macrophages and T-lymphocytes, the proliferation of intimal cells of the arterial wall, the accumulation of lipids and the deposition of extracellular matrix components. For some years, endothelial cells, smooth muscle cells, and macrophages have been accorded crucial roles in the process of atherosclerosis. The mechanisms by which these cells contribute to atherosclerosis include augmented expression of adhesion molecules, as well as secretion of proinflammatory cytokines, matrix metalloproteinases, and tissue factor within human and experimental atheroma. Much evidence supports the role of tissue factor in inciting the thrombosis that causes most acute coronary syndromes. Macrophage content and expression of tissue factor correlate with rupture and instability of the atherosclerotic plaque. Matrix metalloproteinases can digest the plaque's extracellular matrix, and thus impair its stability. Plaque rupture exposes circulating blood components to the tissue factor-rich lipid-core, inciting thrombosis. Despite the increasing appreciation that atherogenesis involves participation of inflammatory pathways within cellular interactions, mediators of local communication between the major cell types within atherosclerotic plaques remain incompletely defined. By early appearance, activated T-cells may act as the orchestrator of atherogenesis. Both soluble and contact-dependent mediators from T-cells may be crucial in the development of this prevalent disease. Recent reports have helped explain some of these questions by pointing to a role of contact dependent interaction between CD40 and CD40 ligand (CD40L, renamed CD154) as a stimulus for atheroma-associated cells. We and others have recently showed that activated T-lymphocytes within the atherosclerotic vessel wall express the CD40 ligand surface molecule, known to play a major role in several immunological pathways. In addition to activated T-lymphocytes, functional CD40 and CD40L are coexpressed by human vascular endothelial cells, smooth muscle cells and human macrophages in vitro as well as in situ in human atherosclerotic lesions. Recent studies indicate that CD40L activates atheroma-associated cells by promoting the expression of molecules thought to be involved in atherosclerosis, such as adhesion molecules, cytokines, matrix metalloproteinases, and tissue factor. Thus, CD40 ligation on these vascular wall cells may promote mononuclear cell recruitment, participate in the weakening of the plaque and set the stage for thrombosis, mechanisms of crucial importance in the process of atherosclerosis. The involvement of the CD40 signaling pathway may play major roles during atherogenesis by regulating antigen-specific T-cell responses to yield activation instead of tolerance, and the presence of functional CD40L on non-leukocytic cells associated with atherosclerotic lesion indicates a novel T-cell-independent route of inflammatory activation, a now well recognized component of atherogenesis. These findings establish a possible crucial role for CD40-CD40L interactions in a prevalent human disease.
Atherosclerosis 1998 Apr
PMID:CD40 signaling in vascular cells: a key role in atherosclerosis? 969 47

The recruitment of mononuclear leukocytes, and the migration, growth and activation of macrophages, lymphocytes and smooth muscle cells within lesions, are critical features of the chronic inflammatory response that typifies atherogenesis. Chemokines are members of a superfamily of small polypeptides that mediate not only migration, but also growth and activation of leukocytes and a variety of other cells. Monocyte chemoattractant and activating protein-1 was the first chemokine to be implicated in leukocyte-mediated inflammation in atherosclerosis. This review emphasizes new information on the potential atherogenic roles of monocyte chemoattractant and activating protein-1 and several other closely related chemokines of the C-C subfamily. We focus particular attention on the newly recognized atherogenic role of a subgroup of closely related chemokines of the C-X-C subfamily that includes interleukin-8 and growth regulated oncogene alpha. We also discuss new studies that reveal how CD40 ligand and certain other stimuli can promote chemokine expression in atherosclerosis.
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PMID:Chemokines and atherosclerosis. 981 93

Stromelysin-3 is an unusual matrix metalloproteinase, being released in the active rather than zymogen form and having a distinct substrate specificity, targeting serine proteinase inhibitors (serpins), which regulate cellular functions involved in atherosclerosis. We report here that human atherosclerotic plaques (n = 7) express stromelysin-3 in situ, whereas fatty streaks (n = 5) and normal arterial specimens (n = 5) contain little or no stromelysin-3. Stromelysin-3 mRNA and protein colocalized with endothelial cells, smooth muscle cells, and macrophages within the lesion. In vitro, usual inducers of matrix metalloproteinases such as interleukin-1, interferon-gamma, or tumor necrosis factor alpha did not augment stromelysin-3 in vascular wall cells. However, T cell-derived as well as recombinant CD40 ligand (CD40L, CD154), an inflammatory mediator recently localized in atheroma, induced de novo synthesis of stromelysin-3. In addition, stromelysin-3 mRNA and protein colocalized with CD40L and CD40 within atheroma. In accordance with the in situ and in vitro data obtained with human material, interruption of the CD40-CD40L signaling pathway in low density lipoprotein receptor-deficient hyperlipidemic mice substantially decreased expression of the enzyme within atherosclerotic plaques. These observations establish the expression of the unusual matrix metalloproteinase stromelysin-3 in human atherosclerotic lesions and implicate CD40-CD40L signaling in its regulation, thus providing a possible new pathway that triggers complications within atherosclerotic lesions.
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PMID:Expression of stromelysin-3 in atherosclerotic lesions: regulation via CD40-CD40 ligand signaling in vitro and in vivo. 1004 48

Activated T lymphocytes accumulate early in atheroma formation and persist at sites of lesion growth and rupture, suggesting that they may play an important role in the pathogenesis of atherosclerosis. Moreover, atherosclerotic lesions contain the Th1-type cytokine IFN-gamma, a potentiator of atherosclerosis. The present study demonstrates the differential expression of the 3 IFN-gamma-inducible CXC chemokines--IFN-inducible protein 10 (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha chemoattractant (I-TAC)--by atheroma-associated cells, as well as the expression of their receptor, CXCR3, by all T lymphocytes within human atherosclerotic lesions in situ. Atheroma-associated endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages (MO) all expressed IP-10, whereas Mig and I-TAC were mainly expressed in ECs and MO, as detected by double immunofluorescence staining. ECs of microvessels within lesions also expressed abundant I-TAC. In vitro experiments supported these results and showed that IL-1beta, TNF-alpha, and CD40 ligand potentiated IP-10 expression from IFN-gamma-stimulated ECs. In addition, nitric oxide (NO) treatment decreased IFN-gamma induction of IP-10. Our findings suggest that the differential expression of IP-10, Mig, and I-TAC by atheroma-associated cells plays a role in the recruitment and retention of activated T lymphocytes observed within vascular wall lesions during atherogenesis.
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PMID:Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. 1052 42

CD40 ligand, a type II transmembrane protein recently renamed CD154, was originally considered restricted to activated T lymphocytes, functioning as a mediator of T cell-dependent B cell activation, proliferation, and differentiation. However, the spectrum of CD154 expression and function has broadened considerably during recent years, establishing new roles as a central mediator of immunity and inflammation for this member of the tumor necrosis factor (TNF) gene superfamily. The emerging picture indicates that ligation of the receptor CD40 via CD154, most potently in its trimeric form, functions in two ways. CD154 modulates physiologic processes, such as T cell-mediated effector functions and general immune responses required for appropriate host defense, but also triggers the expression of pro-inflammatory mediators, such as cytokines, adhesion molecules, and matrix degrading activities, all of which are associated with the pathogenesis of chronic inflammatory diseases, e.g., autoimmune disorders, arthritis, atherosclerosis, and cancer. Accordingly, CD40/CD154 interactions have advanced as a potential therapeutic target for these diseases, whereby two opposing strategies, interruption as well as enhancement of CD40 signaling, are explored for beneficial outcomes.
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PMID:CD154 (CD40 ligand). 1085 99

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.
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PMID:Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. 1086 Sep 49

Chlamydia pneumoniae infection is associated with atherosclerosis and the organism has been identified in arterial lesions. To determine whether T lymphocyte-mediated immune responses to Chlamydia antigens within plaque could contribute to pathogenesis, we have derived T cell lines from atherosclerotic plaques of 32 patients. Culture with IL-2 alone proved insufficient for cellular activation and expansion, but additional stimulation with phytohaemagglutinin (PHA) or recall antigens allowed consistent establishment of T cell lines. Furthermore, in cultures of approx. 500 tissue fragments, Chlamydia organisms proved as effective as other recall antigens in producing outgrowth of arterial T cells (20-25% wells produced T cell lines). Testing the antigen responsiveness of T cell lines showed that those derived using Chlamydia organisms were more likely to respond to Chlamydia (5/29+) than those isolated using other stimuli (6/69+ for PHA; 5/57+ for PPD and tetanus toxoid (TT)). However, lines responsive to each of the recall antigens were observed. Using recombinant Chlamydia antigens, some Chlamydia-specific T cell lines were shown to respond to OMP2 and/or hsp60. Those recognizing Chlamydia hsp60 did not cross-react with human hsp60, but human hsp60-responsive lines were also observed. Thus, atherosclerotic plaque tissue contains a variety of memory T lymphocytes, and amongst these are cells capable of recognizing Chlamydia antigens. In a C. pneumoniae-infected plaque, such T cells may be activated by local antigen and could contribute to the inflammatory process in the arterial wall through CD40 ligand expression and cytokine secretion.
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PMID:T lymphocyte lines isolated from atheromatous plaque contain cells capable of responding to Chlamydia antigens. 1093 Nov 40

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.
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PMID:Absence of CD40 signaling is associated with an increase in intimal thickening after arterial injury. 1123 Jan 5

Inflammation and oxidative stress contribute to the pathogenesis of many human diseases including atherosclerosis. Advanced human atheroma contains high levels of the enzyme myeloperoxidase that produces the pro-oxidant species, hypochlorous acid (HOCl). This study documents increased numbers of myeloperoxidase-expressing macrophages in eroded or ruptured plaques causing acute coronary syndromes. In contrast, macrophages in human fatty streaks contain little or no myeloperoxidase. Granulocyte macrophage colony-stimulating factor, but not macrophage colony-stimulating factor, selectively regulates the ability of macrophages to express myeloperoxidase and produce HOCl in vitro. Moreover, myeloperoxidase-positive macrophages in plaques co-localized with granulocyte macrophage colony-stimulating factor. Pro-inflammatory stimuli known to be present in human atherosclerotic plaque, including CD40 ligand, lysophosphatidylcholine, or cholesterol crystals, could induce release of myeloperoxidase from HOCl production by macrophages in vitro. HOCl-modified proteins accumulated at ruptured or eroded sites of human coronary atheroma. These results identify granulocyte macrophage colony-stimulating factor as an endogenous regulator of macrophage myeloperoxidase expression in human atherosclerosis and support a particular role for the myeloperoxidase-expressing macrophages in atheroma complication and the acute coronary syndromes.
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PMID:Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. 1123 37


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