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)

Platelets are a rich source of different chemokines and express chemokine receptors. CXCL4 is highly abundant in platelets and involved in promoting monocyte arrest from rolling and monocyte differentiation to macrophages. CXCL4 can also associate with CCL5 and amplify its effect on monocytes. The megakaryocyte CXCL7 gene product is proteolytically cleaved into the strong neutrophil chemoattractant, NAP-2, which has also been implicated in repair cell homing to vascular lesions. Platelet adhesion can induce release of CCL2 and CXCL8 from endothelial cells. Conversely, the chemokines CCL17, CCL22, and CXCL12 made by other cells amplify platelet activation. Platelet chemokines enhance recruitment of various hematopoietic cells to the vascular wall, fostering processes such as neointima formation, atherosclerosis, and thrombosis, but also vessel repair and regeneration after vascular injury.
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PMID:Platelet chemokines in vascular disease. 1872 31

Cytomegalovirus (CMV) is associated with atherosclerosis and transplant vascular sclerosis. The aim of this study was to explore the hypothesis that active CMV infection in the vessel wall could be associated with abdominal aortic aneurysm (AAA). We examined the prevalence of CMV in AAA specimens from 22 patients undergoing surgery and, in five cases, characterized the function of smooth muscle cells (SMCs) from the aneurysm in vitro. Twenty-one (95%) of the 22 AAA specimens were CMV positive by a polymerase chain reaction assay, in situ hybridization, or a highly sensitive immunohistochemical staining technique. No positive cells were found in aortas from three CMV-seronegative organ donor cadavers. CMV immediate-early and late antigens were expressed in SMCs in the lesions and were associated with 5-lipoxygenase (5-LO) expression. CMV-positive intimal SMCs migrated 6.6 +/- 1.5 times more efficiently than CMV-negative medial SMCs (p < 0.05). In vitro CMV infection of medial SMCs resulted in a 3.2 +/- 1.2 times increase in migration (p < 0.05). The intimal migration was significantly inhibited by antibodies against basic fibroblast growth factor (bFGF; p < 0.05) in a dose-dependent fashion. Antibodies against platelet-derived growth factor (PDGF)-AB, insulin-like growth factor 1, vascular endothelial growth factor (VEGF), RANTES, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, or interleukin-1beta did not significantly affect intimal SMC migration. However, intimal and medial SMCs secreted similar amounts of bFGF, MCP-1, MIP-1alpha, RANTES, PDGF-AB, PDGF-BB, epidermal growth factor, and VEGF. CMV infection in vitro of intimal and medial cells did not result in significant changes of bFGF or MCP-1 secretion. Since CMV infection can affect several functional parameters in SMCs, including several key factors in infected SMCs, our findings provide support for the hypothesis that CMV contributes to the pathogenesis of abdominal aortic aneurysm.
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PMID:Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic aneurysm. 1908 94

Oxidative modification of low-density lipoprotein (LDL) plays a causative role in the development of atherosclerosis. In this study, we demonstrate that minimally oxidized LDL (mmLDL) stimulates intracellular reactive oxygen species (ROS) generation in macrophages through NADPH oxidase 2 (gp91phox/Nox2), which, in turn, induces production of RANTES and migration of smooth muscle cells. Peritoneal macrophages from gp91phox/Nox2(-/-) mice or J774 macrophages in which Nox2 was knocked down by small interfering RNA failed to generate ROS in response to mmLDL. Because mmLDL-induced cytoskeletal changes were dependent on Toll-like receptor (TLR)4, we analyzed ROS generation in peritoneal macrophages from wild-type, TLR4(-/-), or MyD88(-/-) mice and found that mmLDL-mediated ROS was generated in a TLR4-dependent, but MyD88-independent, manner. Furthermore, we found that ROS generation required the recruitment and activation of spleen tyrosine kinase (Syk) and that mmLDL also induced phospholipase PLCgamma1 phosphorylation and protein kinase C membrane translocation. Importantly, the phospholipase Cgamma1 phosphorylation was reduced in J774 cells expressing Syk-specific short hairpin RNA. Nox2 modulated mmLDL activation of macrophages by regulating the expression of proinflammatory cytokines interleukin-1beta, interleukin-6, and RANTES. We showed that purified RANTES was able to stimulate migration of mouse aortic smooth muscle cells and addition of neutralizing antibody against RANTES abolished the migration of mouse aortic smooth muscle cells stimulated by mmLDL-stimulated macrophages. These results suggest that mmLDL induces generation of ROS through sequential activation of TLR4, Syk, phospholipase Cgamma1, protein kinase C, and gp91phox/Nox2 and thereby stimulates expression of proinflammatory cytokines. These data help explain mechanisms by which endogenous ligands, such as mmLDL, can induce TLR4-dependent, proatherogenic activation of macrophages.
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PMID:Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. 1909 31

Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4) and RANTES (CCL5), triggering monocyte arrest on inflamed endothelium. Homo-oligomerization is required for the recruitment functions of CCL5, and chemokine heteromerization has more recently emerged as an additional regulatory mechanism, as evidenced by a mutual modulation of CXCL8 and CXCL4 activities and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely compromise systemic immune responses, delay macrophage-mediated viral clearance and impair normal T cell functions. Here we determined structural features of CCL5-CXCL4 heteromers and designed stable peptide inhibitors that specifically disrupt proinflammatory CCL5-CXCL4 interactions, thereby attenuating monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects.
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PMID:Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. 1912 57

Chlamydia pneumoniae has during recent years been associated with cardiovascular disease and atherosclerosis. Chemokines, leukocyte adhesion proteins and metalloproteinases are significant for chemotaxis and attachment of leukocytes to vessel walls, and for stability of atherosclerotic plaques. To determine the ability of C. pneumoniae to elicit inflammation in a relevant target host cell, we infected human coronary artery endothelial cells (HCAEC) with a clinical isolate of C. pneumoniae. Extracellular release of five chemokines, two adhesion proteins and a metalloproteinase was measured at different time points after infection using a cytometric bead assay and ELISA. Secretion of IL-8, MCP-1, MIG, IP-10 and ICAM-1 was significantly increased 48 h after C. pneumoniae infection of HCAEC in comparison with uninfected controls. Release of RANTES occurred already 6 h after infection. C. pneumoniae did not elicit release of E-selectin or MMP-1. We conclude that C. pneumoniae induces expression of proinflammatory components in HCAEC, which would promote migration of leukocytes towards endothelial cells. This suggests that C. pneumoniae initiates and propagates vascular inflammation in ways that contribute to coronary artery disease.
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PMID:Expression of chemokines and adhesion molecules in human coronary artery endothelial cells infected with Chlamydia (Chlamydophila) pneumoniae. 1913 11

Inflammation plays a key role in the development of atherosclerosis. Genetic differences in molecules related to inflammation have therefore been linked to the susceptibility for and severity of atherosclerosis. We hypothesized that the additive contribution from different genes of importance for inflammation would enhance the severity of cardiovascular disease. Blood samples were collected from 230 adults admitted for elective coronary angiography. A total of 130 patients had significant (>50%) stenosis in at least one main coronary artery branch and 100 had not. Six polymorphisms in five different genes were analysed: myeloperoxidase (MPO) -129G/A and -463G/A, toll-like receptor 4 (TLR4) Asp299Gly, interleukin-6 (IL6) -174G/C, surfactant protein D (SFTPD) Met11Thr and regulated upon normal T-cell expressed and secreted (CCL5) -403G/A. The IL6 polymorphism was significantly associated (P = 0.017) to angiographic significant coronary artery disease, and this relation remained after adjustment for age, gender, smoking and hypercholesterolaemia (P = 0.007). The TLR4 (P = 0.050) and SFTPD (P = 0.058) polymorphisms were also associated with the presence of coronary stenosis in univariate but not in multivariate analyses. For MPO and CCL5 no associations were found. There was a significant linear association between the number of high-risk gene variants (IL6-174CC, SFTPD 11CC and TLR4 299AA) and the proportion of patients with coronary artery disease (P < 0.0005). Inherited factors related to inflammation may increase susceptibility for severe coronary artery disease. Furthermore, the additive contribution from different inflammatory genetic markers strongly enhances the individual severity of cardiovascular disease.
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PMID:The additive contribution from inflammatory genetic markers on the severity of cardiovascular disease. 1914 Aug 75

Lysophosphatidylcholine (lysoPtdCho) is a component of oxidized low density lipoprotein, and is involved in the pathogenesis of atherosclerosis and inflammation. We studied the effects of lysoPtdCho on cytotoxicity, reactive oxygen species (ROS) production, activation of the extracellular signal-regulated kinase (ERK), mitogen-activated protein kinases and pro-inflammatory gene expression in RAW 264.7 murine macrophage cells. When cells were exposed to lysoPtdCho with various acyl chains in a culture medium containing 10% fetal bovine serum, only 1-linoleoyl (C18:2) lysoPtdCho showed a remarkable cytotoxicity, reaching the highest level at 24 h, and elicited ROS production, suggesting that oxidative stress might be implicated in the cytotoxicity of 1-linoleoyl (C18:2) lysoPtdCho. Presumably in support of this, antioxidants such as magnolol or trolox prevented 1-linoleoyl (C18:2) lysoPtdCho-induced cytotoxicity as well as ROS production, although only partially. Furthermore, the phosphorylation of ERK 1/2 and the expression of pro-inflammatory cytokines such as IL-1beta, CCL2 and CCL5 were augmented by 1-linoleoyl (C18:2) lysoPtdCho. Meanwhile, there was no structural importance of the acyl chain for the cytotoxic action of lysoPtdCho during 10 min incubation in serum-free media. Taken together, it is suggested that in a serum-containing medium, 1-linoleoyl (C18:2) lysoPtdCho can cause a significant cytotoxicity through ROS production, probably accompanied by activation of ERK and induction of related inflammatory cytokines, in RAW 264.7 cells.
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PMID:Lysophosphatidylcholine exhibits selective cytotoxicity, accompanied by ROS formation, in RAW 264.7 macrophages. 1925 37

15-Lipoxygenase-1 (15-LOX-1) has been proposed to be involved in various physiological and pathophysiological activities such as inflammation, atherosclerosis, cell maturation, and tumorigenesis. Asthma and chronic obstructive pulmonary disease are associated with increased expression of 15-LOX-1 in bronchial epithelial cells, but the potential functions of 15-LOX-1 in airway epithelial cells have not been well clarified. To study the function of 15-LOX-1 in bronchial epithelial cells, we ectopically expressed 15-LOX-1 in the human lung epithelial cell line A549. We found that overexpression of 15-LOX-1 in A549 cells leads to increased release of the chemokines MIP-1alpha, RANTES, and IP-10, and thereby to increased recruitment of immature dendritic cells, mast cells, and activated T cells. These results suggest that an increased expression and activity of 15-LOX-1 in lung epithelial cells is a proinflammatory event in the pathogenesis of asthma and other inflammatory lung disorders.
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PMID:15-Lipoxygenase-1 induces expression and release of chemokines in cultured human lung epithelial cells. 1942 75

Hypercholesterolemia is increasingly considered the basis for not only cardiovascular pathologies but also several complications affecting other organs such as lungs. In this study, we examined the effect of hypercholesterolemia on lung integrity using a mouse model (ApoE(-/-)) of high-fat (HF) diet-induced atherosclerosis. A 12-week HF diet regimen induced systemic production of TNF-alpha, IFN-gamma, GMC-SF, RANTES, IL-1alpha, IL-2 and IL-12 with TNF-alpha as the predominant cytokine in ApoE(-/-) mice. Concomitantly, TNF-alpha, IFN-gamma and MIP-1alpha were detected in brochoalveolar lavage (BAL) fluids of these mice, coinciding with lung inflammation consisting primarily of monocytes/macrophages. Such lung inflammation correlated with marked collagen deposition and an increase in matrix metalloproteinase-9 activity in ApoE(-/-)mice without mucus production. Although TGF-beta1 was undetectable in the BAL fluid of ApoE(-/-) mice on HF diet, it showed a much wider tissue distribution compared with that of control animals. Direct exposure of smooth muscle cells to oxidized-LDL, in vitro, induced a time-dependent expression of TNF-alpha. Direct intratracheal TNF-alpha-administration induced a lung inflammation pattern in wild-type mice that was strikingly similar to that induced by HF diet in ApoE(-/-) mice. TNF-alpha administration induced expression of several factors known to be critically involved in lung remodeling, such as MCP-1, IL-1beta, TGF-beta1, adhesion molecules, collagen type-I and TNF-alpha itself in the lungs of treated mice. These results suggest that hypercholesterolemia may promote chronic inflammatory conditions in lungs that are conducive to lung remodeling potentially through TNF-alpha-mediated processes.
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PMID:High-fat diet induces lung remodeling in ApoE-deficient mice: an association with an increase in circulatory and lung inflammatory factors. 1975 57

Low-density lipoprotein (LDL) apheresis is well-established in selected patients with uncontrolled LDL levels. As such treatment affects biomarkers important in atherosclerosis and acute coronary syndromes, we systematically compared the inflammatory response induced by three LDL apheresis columns. Three patients with heterozygous familial hypercholesterolemia participated in a cross-over study with six consecutive treatments with three different LDL apheresis columns: DL-75 (whole blood adsorption), LA-15 (plasma adsorption), and EC-50W (plasma filtration). Biochemical parameters and inflammatory biomarkers, including complement activation products and 27 cytokines, chemokines, and growth factors were measured before and after treatment. Complement was activated through the alternative pathway. The final end product sC5b-9 increased significantly (P < 0.01) and equally with all devices, whereas the anaphylatoxins C3a and C5a were lower by use of the adsorption columns. Hs-CRP was reduced by 77% (DL-75), 72% (LA-15), and 43% (EC-50W). The cytokines were consistently either increased (IL-1ra, IP-10, MCP-1), decreased (IFN-gamma, TNF-alpha, RANTES, PDGF, VEGF), or hardly changed (including IL-6, IL8, MIP-1alphabeta) during treatment. The changes were in general less pronounced with the adsorption columns. All columns reduced LDL significantly and to the same extent. In conclusion, three LDL-apheresis devices with equal cholesterol-lowering effect differed significantly with respect to the inflammatory response.
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PMID:Different inflammatory responses induced by three LDL-lowering apheresis columns. 1992 64


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