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 human cytomegalovirus (HCMV) has been implicated in the acceleration of vascular disease for some time. The development of vascular disease involves a chronic inflammatory process with many contributing factors, and of these, chemokines and their receptors have recently been identified as key mediators. Interestingly, HCMV encodes four potential chemokine receptors (US27, US28, UL33 and UL78). Of these virally-encoded chemokine receptors, US28 has been the most widely characterized. US28 binds many of the CC-chemokines, and this class of chemokines contributes to the development of vascular disease. Importantly, HCMV infection mediates in vitro SMC migration, which is dependent upon expression of US28 and CC-chemokine binding. US28 and the US28 functional homologues that are capable of inducing the migration of SMC represent potential targets in the treatment of CMV-accelerated vascular disease such as atherosclerosis, restenosis, and transplant vascular sclerosis.
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PMID:The HCMV chemokine receptor US28 is a potential target in vascular disease. 1245 11

Human cytomegalovirus (HCMV) encodes a G protein-coupled receptor (GPCR), named US28, which shows homology to chemokine receptors and binds several chemokines with high affinity. US28 induces migration of smooth muscle cells, a feature essential for the development of atherosclerosis, and may serve as a co-receptor for human immunodeficiency virus-type 1 entry into cells. Previously, we have shown that HCMV-encoded US28 displays constitutive activity, whereas its mammalian homologs do not. In this study we have identified a small nonpeptidergic molecule (VUF2274) that inhibits US28-mediated phospholipase C activation in transiently transfected COS-7 cells and in HCMV-infected fibroblasts. Moreover, VUF2274 inhibits US28-mediated HIV entry into cells. In addition, VUF2274 fully displaces radiolabeled RANTES (regulated on activation normal T cell expressed and secreted) binding at US28, apparently with a noncompetitive behavior. Different analogues of VUF2274 have been synthesized and pharmacologically characterized, to understand which features are important for its inverse agonistic activity. Finally, by means of mutational analysis of US28, we have identified a glutamic acid in transmembrane 7 (TM 7), which is highly conserved among chemokine receptors, as a critical residue for VUF2274 binding to US28. The identification of a full inverse agonist provides an important tool to investigate the relevance of US28 constitutive activity in viral pathogenesis.
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PMID:Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. 1245 73

(1) Chemokines play a central role in the pathogenesis of atherosclerosis, contributing to leukocyte recruitment, angiogenesis and also proliferation and migration of smooth muscle cells into atherosclerotic plaques. (2) Leukocytes and endothelial cells are an important source of chemokines, and many of the risk factors associated with atherosclerosis increase chemokine expression. There is now a body of evidence to suggest that interactions between cells such as leukocytes and endothelial cells amplify chemokine release, and this may contribute to sustained chemokine generation in inflammatory conditions. (3) This article summarises, briefly, what is currently known about chemokines release. A number of important pharmacological strategies used in the treatment of atherosclerosis inhibit chemokine release and the extent to which this may contribute to their therapeutic effect will be discussed. Understanding the mechanisms controlling chemokine expression is essential for the design of specific therapeutic interventions in atherosclerosis.
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PMID:Regulation of chemokine expression in atherosclerosis. 1248 33

Macrophages play an important role in the pathogenesis of atherosclerosis, for which monocyte chemoattractant protein (MCP)-1 and CCR2 chemokine receptors may be involved. The authors have recently demonstrated that propagermanium exerts inhibitory effect on the CCR2 receptors. In the current study, the authors examined whether the organic germanium suppresses the MCP-1-induced monocyte migration in vitro and the development of atherosclerosis in WHHL rabbits in vivo. In the in vitro experiment, propagermanium concentration-dependently suppressed the MCP-1-induced migration of THP-1 cells. In the in vivo experiment, 20 WHHL rabbits were randomly divided into two groups; one group was treated with oral administration with propagermanium (9 mg/kg/day) for 3 months, and another group served as a control (n = 10 each). After 3 months, the aorta was isolated and stained with oil red O staining, and neointimal formation was quantified. Macrophage accumulation in the aorta was also evaluated by immunostaining. Long-term treatment with propagermanium did not affect the serum lipid profiles. However, the treatment significantly suppressed the oil red O-positive area of the total aorta (p < 0.05). Similarly, propagermanium significantly suppressed the intimal lesions (maximal intimal thickness and intimal area) and macrophage staining-positive area (all p < 0.05). A significant positive correlation was noted between macrophage staining-positive area and intimal lesions (p < 0.0001). These results indicate that long-term treatment with propagermanium suppresses the development of atherosclerosis in WHHL rabbits, suggesting its usefulness for the treatment of atherosclerotic vascular disease in humans.
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PMID:Long-term treatment with propagermanium suppresses atherosclerosis in WHHL rabbits. 1254 76

The hallmark of early atherosclerosis is the accumulation of lipid-laden macrophages in the subendothelial space. Circulating monocytes are the precursors of these "foam cells," and recent evidence suggests that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Fractalkine (FK) is a structurally unusual chemokine that can act either as a soluble chemotactic factor or as a transmembrane-anchored adhesion receptor for circulating leukocytes. A polymorphism in the FK receptor, CX(3)CR1, has been linked to a decrease in the incidence of coronary artery disease. To determine whether FK is critically involved in atherogenesis, we deleted the gene for CX(3)CR1 and crossed these mice into the apoE(-/-) background. Here we report that FK is robustly expressed in lesional smooth muscle cells, but not macrophages, in apoE(-/-) mice on a high-fat diet. CX(3)CR1(-/-) mice have a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation. Taken together, these data provide strong evidence that FK plays a key role in atherogenesis.
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PMID:Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. 1269 29

The accumulation of macrophages and T lymphocytes in vessel walls is a hallmark of atherogenesis. It has recently been demonstrated in mouse models of atherosclerosis that full disease potential is dependent on several regulators of leukocyte trafficking, including the chemokine monocyte chemotactic protein 1 (MCP-1) and the chemokine receptors CCR2 and CXCR2. A possible role for the chemokine receptor CCR5 in atherogenesis has been suggested by CCR5 expression on macrophages, T cells, coronary endothelial cells and aortic smooth muscle cells and by the presence of CCR5 ligands in atherosclerotic plaques. Moreover, individuals who are naturally deficient in CCR5 were reported to be at reduced risk for severe coronary artery disease (CAD) and early myocardial infarction (MI). To investigate whether CCR5 is pro-atherogenic in mice, we generated CCR5-deficient mice and crossed them with atherosclerosis-prone apoE-deficient mice. Although CCR5-deficient mice exhibit defects in induced macrophage trafficking, mean atherosclerotic lesion area did not differ significantly between apoE-deficient mice and apoE/CCR5-deficient mice after 16 weeks on a diet of normal chow. Ribonuclease protection assays (RPA) on RNA isolated from plaques from both apoE-deficient and apoE/CCR5-deficient animals showed strong signals for the macrophage marker F4/80 but no evidence for expression of prominent markers of T and B lymphocytes. These results indicate that the early stages of plaque formation in this model of lipid-mediated atherogenesis do not depend on CCR5.
Atherosclerosis 2003 Mar
PMID:CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice. 1261 65

Inappropriate inflammation is a component of a wide range of human diseases, including autoimmune disease, atherosclerosis, osteoporosis and Alzheimer's disease. Chemokines play an important role in orchestrating leukocyte recruitment during inflammation, and therefore represent an important target for anti-inflammatory therapies. Unfortunately, the chemokine system is complex, with about 50 ligands and 20 receptors, often acting with redundancy, making selection of appropriate specific antagonists difficult. One approach to overcoming this difficulty may be the development of broad-spectrum chemokine inhibitors (BSCIs). Here we review the present state of knowledge on BSCIs, including their activity in vitro and their anti-inflammatory effects in vivo, and discuss the future development of BSCIs as anti-inflammatory therapies for use in the clinic.
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PMID:Broad-spectrum chemokine inhibitors (BSCIs) and their anti-inflammatory effects in vivo. 1266 38

The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD.
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PMID:Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. 1269 29

Various herpes- and poxviruses contain DNA sequences encoding proteins with homology to cellular chemokine receptors, which belong to the family of G protein-coupled receptors (GPCRs). Since GPCRs play a crucial role in cellular communication and chemokine receptors play a prominent role in the immune system, the virally encoded GPCRs may be crucial determinants of viral action. The Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus 8), implicated in the pathogenesis of Kaposi's sarcoma (KS), a highly vascularized tumor, encodes a GPCR, referred to as ORF74. This virally encoded receptor was found to induce tumorigenesis and transgenic expression of ORF74 induces an angioproliferative disease resembling KS. Cytomegalovirus (CMV), suggested to play a role in atherosclerosis, encodes four GPCRs, among which US28. This virally encoded GPCR is able to induce migration of smooth muscle cells, a feature essential for the development of atherosclerosis. Remarkably, the KSHV and some CMV-encoded GPCRs display constitutive activity, while their cellular homologs do not. It remains to be determined whether this phenomenon contributes to the pathogenesis of viral action. Also, the family of poxviruses encodes GPCRs of which the function is not clear yet. In this review we will give an overview of the different virally encoded GPCRs, and discuss their putative role in viral action and potential as drug target.
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PMID:Virally encoded G protein-coupled receptors: targets for potentially innovative anti-viral drug development. 1281 50

Expression of membrane-bound CX3CL1, a CX(3)C chemokine, can be strongly induced by inflammatory cytokines in primary endothelial cells, mediating capture and tight adhesion of cells, such as monocytes, that carry the CX(3)CR1 receptor. Here, we measured CX3CL1 mRNA and protein induction by human aortic smooth muscle cells (SMCs), another major component of vessel walls, in response to inflammatory stimuli, and analyzed the effect of membrane-bound CX3CL1 on monocyte adhesion, tissue factor (TF) expression, and tumor necrosis factor-alpha (TNF-alpha) released. In human vascular SMCs, CX3CL1 transcripts were induced after 4h of stimulation with a combination of TNF-alpha and interferon-gamma. Cell-associated and shedded CX3CL1 were measured with a specific ELISA, showing that only 30% of the protein was cleaved from the membrane. Expression of CX3CL1 by SMC increased adhesion of monocytic cells, an effect, which was blocked by soluble CX3CL1. Interestingly, monocyte adhesion to CX3CL1-coated plates partially inhibited lipopolysaccharide-induced TF expression and TNF-alpha release. Thus, CX3CL1, in addition to its adhesive/chemotactic functions, directly promotes monocyte antiinflammatory and antiprocoagulant responses. This could have important implications in clinical settings such as atherosclerosis, in which SMCs and monocytic cells are in close proximity.
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PMID:Fractalkine/CX3CL1 production by human aortic smooth muscle cells impairs monocyte procoagulant and inflammatory responses. 1282 4


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