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)

The migration of leukocytes into inflamed peripheral tissues and lymphoid organs involves a cascade of molecular events finely regulated by cell adhesion molecules and chemokines. Fractalkine/CX3CL1 is a membrane-bound chemokine that functions not only as a chemoattractant but also as an adhesion molecule, and is expressed on endothelial cells activated by proinflammatory cytokines. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes including NK cells and cytotoxic effector T cells (T(CE)), mature monocytes/macrophages, and mucosal dendritic cells, all of which play important roles in elimination of pathogens and cancer cells. Recently, accumulating evidence in both clinical studies and animal disease models has shown that fractalkine is also involved in the pathogenesis of various chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. This article reviews the unique functions of fractalkine and its pathophysiological roles in various clinical conditions.
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PMID:[Fractalkine and inflammatory diseases]. 1599 76

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

In this review, we first briefly introduce the reader to our autoimmune hypothesis for the development of atherosclerosis based on experimental and clinical data. This hypothesis postulates that humoral and cellular immunity against heat-shock protein 60 (HSP60), a phylogenetically highly conserved stress protein, is the mechanism that initiates atherogenesis. We then turn to our investigations of arterial specimens from children and young adults. These clearly show that mononuclear cell infiltrations of the intimal layer already occur before the emergence of clear-cut atherosclerotic lesions, a phenomenon we have termed vascular-associated lymphoid tissue (VALT). In early lesions analyzed within the framework of the Pathological Determinants of Atherosclerosis in Youth (PDAY) study, T lymphocytes proved to be a major cellular constituent. In the Bruneck Study, a large, prospective atherosclerosis-prevention study in adults aged 40 years and older, we found a highly significant correlation between serum anti-HSP60 antibody titers and the occurrence and extent of sonographically demonstrable atherosclerotic lesions. However, no such correlation emerged with respect to HSP60-reactive T cells in the peripheral blood. In contrast, the similar Atherosclerosis Risk-Factors in Male Youngsters (ARMY) study, performed on 17- to 18-year-old volunteers, showed a highly statistically significant correlation between arterial intima-media thickening and HSP60 reactivity among peripheral T cells and (less pronounced) anti-HSP60 antibodies, even at this young age. We take this as indirect evidence that both T cell and B cell immunity against HSP60 plays a major role in the earliest stages of the disease. Because VALT can already be observed in healthy children and young adults, we hypothesize that T cells initiate the disease and that humoral antibodies play a facilitating, accelerating role. Finally, we provide initial evidence that smoking, as the most important risk factor for atherogenesis, also exerts its disease-inducing and disease-promoting effects by inducing HSP60 expression by vascular endothelial cells.
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PMID:Anti-HSP60 immunity is already associated with atherosclerosis early in life. 1612 74

G2A is a G protein-coupled receptor that is predominantly expressed in lymphoid tissues and macrophages. G2A can be induced by diverse stimuli to cause cell cycle arrest in the G(2)/M phase in pro-B and T cells. G2A is also expressed in macrophages within atherosclerotic lesions, suggesting G2A involvement in atherosclerosis. Recently, G2A was discovered to possess proton-sensing ability. In this paper, we report another function of G2A, that is, as a receptor for 9-hydroxyoctadecadienoic acid (9-HODE) and other oxidized free fatty acids. G2A, expressed in CHO-K1 or HEK293 cells, showed 9-HODE-induced intracellular calcium mobilization, inositol phosphate accumulation, inhibition of cAMP accumulation, [(35)S]guanosine 5'-3-O-(thio)triphosphate binding, and MAP kinase activation. Furthermore, G2A was activated by various oxidized derivatives of linoleic and arachidonic acids, but it was weakly activated by cholesteryl-9-HODE. Oxidized phosphatidylcholine (1-palmitoyl-2-linoleoyl) when hydrolyzed with phospholipase A(2) also evoked intracellular calcium mobilization in G2A-expressing cells. These results indicate that G2A is activated by oxidized free fatty acids produced by oxidation and subsequent hydrolysis of phosphatidylcholine or cholesteryl linoleate. Thus, G2A might have a biological role in diverse pathological conditions including atherosclerosis.
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PMID:Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. 1623 15

Atherosclerosis is nowadays generally accepted as an inflammatory disease but the mechanism of its origin and development have not yet been fully clarified. The present review focuses on the role of the local immune system as one of the key players in the pathogenesis of the complex process. Its part represented by vascular-associated lymphoid tissue (VALT) within the arterial wall participates directly in the vascular wall's homeostatis. Its inordinate activation during ontogenic development of an individual, this formerly defensive and physiologic mechanism transform into a pathological process resulting in an impairing inflammation. Hsp60, CRP and oxidized or otherwise modified LDL are serious candidates for triggering these pathological changes. The principal role is played by anti-Hsp60 antibodies and by shear stress originating on the surface of endothelium due to blood flow. The experimental and clinical data supporting this immunological hypothesis of atherosclerosis are discussed.
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PMID:Defects in regulation of local immune responses resulting in atherosclerosis. 1629 29

Our understanding of the molecular signaling pathways regulating the initiation and progression of atherosclerosis or remodeling in response to injury has begun to cross the boundaries from regulation of well-described canonical pathways to the interplay between these pathways. The focus of this review is to summarize our current understanding of a finite group of transcription factors and kinases involved in vascular injury and atherosclerosis, including nuclear factor-kappaB (NF-kappaB), early growth response factor-1 (Egr-1), activator protein-1 (AP-1), hypoxia inducible factor-1alpha (HIF-1alpha), homeobox, and T cell factor/lymphoid enhancer factor (Tcf-Lef), as well as the kinases janus kinase/signal transducers and activators of transcription (JAK/STAT), protein kinase C (PKC), p38, Rho, ERK5, JNK, p44/p42, and phosphoinositide 3 (PI3) kinase/AKT.
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PMID:Transcription factor and kinase-mediated signaling in atherosclerosis and vascular injury. 1664 Sep 63

Atherosclerosis is an inflammatory disease of large arteries. Flow cytometry of aortic cell suspensions showed that B and T lymphocytes and some macrophages and dendritic cells are already present in the adventitia of normal/noninflamed mouse aortas. Adoptively transferred lymphocytes constitutively homed to the aorta and resided within the adventitia up to 7 d after transfer. Lymphocyte trafficking into normal/noninflamed or atherosclerosis-prone aortas was partially L-selectin dependent. Antigen-activated dendritic cells induced increased T lymphocyte proliferation within the aorta 72 h after adoptive transfer. During progression of atherosclerosis in apolipoprotein-E-deficient mice, the total number of macrophages, T cells, and dendritic cells, but not B cells, increased significantly. This alteration in immune cell composition was accompanied by the formation of tertiary lymphoid tissue in the adventitia of atherosclerotic aortas. These results demonstrate that lymphocytes already reside within the normal/noninflamed aorta before the onset atherosclerosis as a consequence of constitutive trafficking. Atherosclerosis induces the recruitment of macrophages and dendritic cells that support antigen presentation.
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PMID:Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. 1668 95

Antigen-presenting cells (APCs) are involved in the development of atherosclerosis, whose complications represent the main cause of death in diabetic patients. Nevertheless, their role in atherogenesis is poorly understood. We compared the number of circulating monocyte and dendritic cell (DC) subsets as well as their capacity to produce inflammatory cytokines IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) in type 2 diabetic men with (n=11) and without (n=44) chronic atherosclerotic complications. Identification and enumeration of peripheral blood (PB) lymphoid subsets, monocytes, myeloid (CD33strong+), CD16+, and plasmacytoid (CD33-/dim+) DCs as well as of their spontaneous and stimulated production of IL-1beta, IL-6, and TNF-alpha were performed at the single-cell level by flow cytometry. Our results show that type 2 diabetic men with atherosclerotic complications display a significantly reduced spontaneous secretion of IL-6 by monocytes and CD16+ DCs and of TNF-alpha by CD16+ DCs as compared to patients without atherosclerotic complications. Spontaneous secretion of IL-1beta by monocytes and CD16 DCs and of IL-6 by CD33+ and plasmacytoid DCs was detected in patients without atherosclerotic complications but not in the other patients with complications. Taken together, these results indicate that type 2 diabetic men with atherosclerotic complications display both quantitatively and functionally impaired immunological responses by circulating APCs. The decreased patterns of inflammatory cytokine production by these cells may influence the inflammatory response mediated by APCs as well as the antigen-specific responses mediated by other cells such as T cells.
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PMID:Decreased production of inflammatory cytokines by circulating monocytes and dendritic cells in type 2 diabetic men with atherosclerotic complications. 1718 73

Arterial inflammation is a significant component of atherosclerotic disease-specific immune responses directed against autoantigens or pathogen-derived antigens in the vascular wall could initiate and/or maintain atherosclerotic processes. Atherosclerosis is now regarded as a chronic inflammatory disease. Developing in response to injury in the vessel wall, it is characterized by the infiltration of mononuclear lymphocytes into the intima, local expansion of vascular smooth muscle cells, and accumulation of extracellular matrix. A number of potential mechanisms have been implicated in the development of inflammatory reactions in the vascular system. Adventitia provides cells and molecules with the ability to influence neointimal formation and vascular remodeling implemented in part by vasa vasorum. We hypothesize that lymphatic vessels, existing in adventitia in the atherosclerotic artery, could drain local inflammatory cells and cytokines to the lymphatic nodes and lymphoid tissues where inflammatory cells can be sensitized and activated. Or, blood vessels may deliver sensitized inflammatory cells and cytokines to the inflammatory site of the vascular wall. Therefore, both lymphatic and blood vessels constitute a complete circle of immune response, whereby the inflammatory cells and cytokines are effectively delivered to tissues and their effects magnified. Under certain circumstances, this situation may lead to a vicious circle of inflammation such as in atherosclerosis, resulting in perpetuating intimal hyperplasia and vascular remodeling. Inhibition of lymphangiogenesis may interrupt this self-perpetuating vicious circle of inflammation in atherosclerosis and provide a new approach to the prevention and treatment of the disease.
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PMID:Adventitial lymphatic vessels -- an important role in atherosclerosis. 1782 1

Chemokines are low-molecular-weight proteins that attract leukocytes and other cell types, via interaction with G protein-coupled receptors. Chemokines control leukocyte migration not only during inflammatory processes, but also throughout ontogeny and differentiation of lymphoid tissues. They have been involved in the pathogenesis of numerous diseases, such as human immunodeficiency virus infection, allergy, atherosclerosis, cancer, and autoimmunity. The number of studies focusing on chemokine biology is expanding exponentially. For example, searching PubMed for the terms "thyroid" and "chemokine" retrieved 1 article in 1980s, 18 articles in 1990s, and 81 articles from 2000 to July 2007. This review will focus on studies analyzing the role of chemokine in autoimmune thyroiditis (Graves' disease and Hashimoto's thyroiditis), performed in both patients and experimental animals. The goal is to emphasize how a better understanding of chemokine biology has advanced our knowledge of the pathogenesis of autoimmune thyroiditis.
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PMID:Chemokine orchestration of autoimmune thyroiditis. 1791 May 27


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