UMLS:C0004153 - FACTA Search

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 aim of the present study was to assess the genetic risk for atherothrombotic cerebral infarction (ACI) in men and women separately as well as in individuals with or without conventional risk factors for atherosclerosis and thereby to contribute to the personalized prevention of ACI. The study population comprised 2705 unrelated Japanese individuals (1244 men, 1461 women), including 636 subjects (372 men, 264 women) with ACI. Subjects with ACI and controls either had or did not have conventional risk factors for atherosclerosis, including hypertension, hypercholesterolemia, and diabetes mellitus. The genotypes for 202 polymorphisms of 152 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis and a stepwise forward selection procedure revealed that 11 different polymorphisms were significantly (P < 0.005) associated with ACI in women or men or in individuals with or without hyper-tension, hypercholesterolemia, or diabetes mellitus: the 584C-->T polymorphism of LIPG, 5665G-->T of EDN1, and G-->A of CCL11 in women; 677C-->T of MTHFR, 1323C-->T of ITGB2, 3932T-->C of APOE, and -231A-->G of EDNRA in men; -572 G -->C of IL6 in hypertensive individuals; -403G-->A of CCL5 and G-->A of COMT in individuals with hypercholesterolemia; and 3932T--> C of APOE and A-->G of TNFSF4 in diabetic individuals. Polymorphisms associated with ACI may thus differ between women and men as well as among individuals with different risk factors. Stratification of subjects on the basis of sex or conventional risk factors for atherosclerosis may therefore be important in order to achieve the personalized prevention of ACI with the use of genetic information.
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PMID:Genetic risk for atherothrombotic cerebral infarction in individuals stratified by sex or conventional risk factors for atherosclerosis. 1701 17

IgG Fc receptors (FcgammaRs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E-deficient mice (apoE(-/-)) with FcgammaR gamma chain-deficient mice (gamma(-/-)). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE(-/-) control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49+/-6% and 56+/-8%, respectively, compared with the content in apoE(-/-) lesions. Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activated Normal T-cell Expressed and Secreted), and intercellular adhesion molecule-1 (ICAM-1) and the activation of nuclear factor-kappaB (NF-kappaB) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both gamma(-/-) and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-kappaB activation. ApoE(-/-) mice have higher levels of activating FcgammaRI and FcgammaRIIIA, and inhibitory FcgammaRIIB, compared with wild-type mice. The DKO mice express only the inhibitory FcgammaRIIB receptor. We conclude that FcgammaR deficiency limits development and progression of atherosclerosis. In addition to leukocytes, FcgammaR activation in VSMCs contributes to the inflammatory process, in part, by regulating chemokine expression and leukocyte invasion of the vessel wall. These results underscore the critical role of FcgammaRs in atherogenesis and support the use of immunotherapy in the treatment of this disease.
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PMID:Fcgamma receptor deficiency confers protection against atherosclerosis in apolipoprotein E knockout mice. 1712 44

Undoubtedly, platelets are key elements in the regulation of thrombosis and haemostasis. Along with their primary task to prevent blood loss from injured vessels, platelets have emerged as regulators of a variety of processes in the vasculature. Multiple challenges, from the contact and adhesion to subendothelial matrix after injury of the vessel wall, to interactions with blood cells in inflammatory conditions, result in platelet activation with concomitant shape change and release of numerous substances. Among these, chemokines have been found to modulate several processes in the vasculature, such as atherosclerosis and angiogenesis. In particular, the chemokines connective tissue activating protein III (CTAP-III) and its precursors, or truncation products (CXCL7), platelet factor 4, (PF4, CXCL4) and its variant PF4alt (CXCL4L1) or regulated upon activation and normal T cell expressed and secreted (RANTES, CCL5), have been investigated thoroughly. Defined common properties as their aptitude to bind glycosaminoglycans or their predisposition to associate and form homooligomers are pre-requisites for their role in the vasculature and function in vivo. The current review summarizes the development of these single chemokines, and their cooperative effects that may in part be dependent on their physical interactions.
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PMID:Platelet-derived chemokines in vascular biology. 1747 80

Carotid artery stenosis (CS) is a well-established risk factor for stroke. Increased proinflammatory chemokines, enhanced metallothionein (MT), and altered metal homeostasis may play roles in atherosclerosis progression and plaque destabilization. MT may sequester zinc during chronic inflammation, provoke zinc deficiency, and modulate NK cell cytotoxicity. A recent investigation of older patients with diabetes and atherosclerosis showed an association between the -209 A/G MT2A polymorphism, CS, and zinc status. In this study, we evaluated the relationship between two MT2A polymorphisms (-209 and + 838 locus), metal status, and inflammatory/immune response in older patients with CS only (the CS1 group) or with CS and previous cerebrovascular episodes (transient ischemic attack or stroke) (the CS2 group). A total of 506 individuals (188 CS1, 100 CS2, and 218 healthy controls) were studied. Atherosclerotic patients (CS1 and CS2) showed increased levels of MT, MCP-1, and RANTES, reduced NK cell cytotoxicity, and altered trace element concentrations (zinc, copper, magnesium, iron). The +838 C/G MT2A polymorphism was differently distributed in CS1 and CS2 patients, who displayed the GG genotype (C-) with significantly higher frequency than elderly controls. C- carriers showed increased MCP-1 and decreased NK cell cytotoxicity, CD56+ cells, and intracellular zinc availability along with decreased zinc, copper, and magnesium content in erythrocytes and increased iron in plasma. C- carriers also showed a major incidence of soft carotid plaques. In conclusion, the +838 C/G MT2A polymorphism seems to influence inflammatory markers, zinc availability, NK cell cytotoxicity, and trace element status, all of which may promote CS development.
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PMID:The +838 C/G MT2A polymorphism, metals, and the inflammatory/immune response in carotid artery stenosis in elderly people. 1762 11

Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1-/- mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)-salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in several cells, including some immune cells. Accordingly, adoptive transfer of T cells lacking the angiotensin type I receptor or a functional NADPH oxidase resulted in blunted angiotensin II-dependent hypertension and decreased aortic superoxide production. Angiotensin II increased T cell markers of activation and tissue homing in wild-type, but not NADPH oxidase-deficient, mice. Angiotensin II markedly increased T cells in the perivascular adipose tissue (periadventitial fat) and, to a lesser extent the adventitia. These cells expressed high levels of CC chemokine receptor 5 and were commonly double negative (CD3+CD4-CD8-). This infiltration was associated with an increase in intercellular adhesion molecule-1 and RANTES in the aorta. Hypertension also increased T lymphocyte production of tumor necrosis factor (TNF) alpha, and treatment with the TNFalpha antagonist etanercept prevented the hypertension and increase in vascular superoxide caused by angiotensin II. These studies identify a previously undefined role for T cells in the genesis of hypertension and support a role of inflammation in the basis of this prevalent disease. T cells might represent a novel therapeutic target for the treatment of high blood pressure.
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PMID:Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. 1787 76

Atherosclerosis is a chronic inflammatory disease of the arterial wall and an increasing body of evidence suggests that the immune system actively participates in the initiation, progression and persistence of atherosclerosis. Different types of leukocytes such as T and B lymphocytes, natural killer cells (NK) and NKT cells, macrophages, dendritic cells and mast cells have been found within atherosclerosis-prone aortas. The mechanisms of monocyte recruitment have been partially characterized and involve P-selectin, E-selectin, VCAM-1, ICAM-1 and JAM-A. CXCL1, CCL5, CXCL4, CXCL7 and MIF are also implicated in monocyte trafficking into aortas. Recently it has been reported that Ly6C(high) and Ly6C(low) monocyte subsets differently use CCL2, CX3CL1 and CCL5 for their homing into atherosclerotic aortas. T and B lymphocytes constitutively migrate into the normal and atherosclerotic aortic wall in an L-selectin-dependent manner. Recent studies suggest an important role of CCL5, CXCL10, CXCL16, CXCR6 and MIF in T cell influx into the atherosclerotic wall. However, there is little information available on the mechanisms of recruitment of other types of the immune cells such as NK, NKT and mast cells. In this review we shall summarize what is known about leukocyte recruitment into the aortic wall during atherosclerosis with a focus on mouse model systems.
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PMID:Leukocyte influx in atherosclerosis. 1822 Jul 1

Our view of white adipose tissue (WAT) has changed over the last decade, from an inert triglyceride storage tissue to a highly active metabolic organ. Indeed, WAT secretes proinflammatory cytokines such TNF-a, interleukin-1 (IL-1), interleukin-1 receptor antagonist (IL-1Ra), and interleukin-6 (IL-6), and chemokines such as monocyte chemoattractant protein-1 (MCP-1), interferon gamma inducible protein 10 (IP-10), interleukin-8 (IL-8), RANTES, and peptides with hormone-like actions such as adiponectin, leptin and resistin. Through their paracrine actions these factors contribute to local WAT inflammation, neoangiogenesis and differentiation. On entering the systemic circulation they can contribute to creating or maintaining a systemic inflammatory state, hypertension and insulin resistance, and can also affect central control of food intake. When located around organs such as the kidney, heart and blood vessels, WAT can adversely affect organ function by secreting cytokines and chemokines. For example, perivascular WAT which secretes proatherogenic cytokines and chemokines and which is present around large and medium-sized arteries, could contribute to the development of atherosclerotic lesions by attracting inflammatory cells and stimulating neoangiogenesis, thereby amplifying the chronic vascular inflammation which is the hallmark of atherosclerosis.
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PMID:[White adipose tissue, inflammation and atherosclerosis]. 1822 44

TNFalpha (TNF) critically regulates inflammation-driven atherosclerosis. Because the transmembrane (tmTNF) and soluble (sTNF) forms of TNF possess distinct immuno-modulatory properties, we hypothesized that they might differentially regulate atherosclerosis progression. Three groups of male ApoE(-/-) mice were studied: one expressing wild-type TNF (WT-TNF); one expressing exclusively a mutated non-cleavable form of TNF (KI-TNF); and one deficient in TNF (KO-TNF). Mice aged 5 weeks were fed the high-fat diet for 5 (T5) and 15 weeks (T15) or a standard chow diet for 15 weeks. At T5, in mice fed the high-fat diet, no significant differences in lesion area were observed among the three groups, either in valves or in aortas. At T15, lesion areas in valves were significantly lower in KO-TNF mice compared with those in WT-TNF mice, whereas in KI-TNF mice, they were intermediate between KO- and WT-TNF mice but not significantly different from these two groups. In aortas, lesions in KI-TNF were comparable to those of KO-TNF, both being significantly lower than those in WT-TNF. Theses differences were not linked to circulating lipids, or to macrophage, actin, and collagen contents of lesions. At T15, in mice fed the chow diet, lesion areas in valves and the aortic arch were not significantly different between the three groups. Levels of IL-6, IFNgamma, IL-10, and Foxp3 mRNAs in spleens and production of IL-6, IL-10, MCP-1, RANTES, and TNFR-2 by peritoneal macrophages at T15 of the high-fat diet showed a decrease in pro-inflammatory status, more marked in KO-TNF than in KI-TNF mice. Apoptosis was reduced only in KO-TNF mice. In conclusion, these data show that TNF effects on atherosclerosis development are detectable at stages succeeding fatty streaks and that wild-type TNF is superior to tmTNF alone in promoting atherosclerosis. TNF-dependent progression of atherosclerosis is probably linked to the differential production of pro-inflammatory mediators whether tmTNF is preponderant or essentially cleaved.
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PMID:Progression of atherosclerosis in ApoE-deficient mice that express distinct molecular forms of TNF-alpha. 1824 29

The immunoregulatory cytokine IL-10 plays an essential role in down-modulating adaptive and innate immune responses leading to chronic inflammatory diseases. In contrast, cysteinyl leukotrienes (cysLTs), important proinflammatory mediators of cell trafficking and innate immune responses, are thought to enhance immune reactions in the pathogenesis of diseases, such as bronchial asthma, atherosclerosis, and pulmonary fibrosis. The aim of this study was to determine the IL-10 regulatory role in cysLT-induced activation of human monocytes and monocyte-derived dendritic cells. Herein we show that cysLT-induced activation and chemotaxis of human monocytes and monocyte-derived immature dendritic cells (iDC) are inhibited by IL-10 pretreatment. IL-10 down-regulated cysLT type 1 and 2 receptors' mRNA in a time- and concentration-dependent fashion. cysLT-induced activation of monocytes and iDCs measured by intracellular calcium flux and immediate-early gene expression (FBJ murine osteosarcoma viral oncogen homolog B and early growth response-2) was potently decreased by IL-10 and by the cysLT antagonist MK571. Chemotaxis of monocytes and iDCs to increasing concentrations of leukotriene D(4) (LTD(4)) was also inhibited by IL-10. LTD(4) enhanced iDC migration in response to CCL5. IL-10 selectively inhibited LTD(4)-induced chemotaxis without affecting migration to CCL5. These data indicate that cysLT-induced activation of human monocytes and dendritic cells may be specifically inhibited by IL-10, suggesting a direct link between the 5-lipoxygenase proinflammatory pathway and IL-10 regulatory mechanisms. Antileukotriene therapies may reproduce some regulatory mechanisms played by IL-10 in inflammatory processes.
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PMID:IL-10 inhibits cysteinyl leukotriene-induced activation of human monocytes and monocyte-derived dendritic cells. 1849 Jul 62

The fundamental importance of chemokines for atherogenesis, progression, and destabilization of atherosclerotic plaques is now widely appreciated, but the degree of complexity, specificity, and cooperativity harnessed by these signal molecules to govern atherogenic cell recruitment and homeostasis is still being refined. Since the role of chemokines in atherosclerotic vascular disease has been reviewed in this journal, significant progress has been accomplished in defining the regulation of chemokine expression and function in atherosclerosis. In this update, we will highlight these recent developments, in particular the identification of components regulating the transcriptional machinery of the proatherogenic chemokine CCL5, distinct roles of its receptors CCR1 and CCR5 in plaque formation and immunobalance, and differential site- and stage-specific effects of T cell-activating chemokines and their receptors, eg, CXCL10 and CXCR3. The contribution of the transmembrane chemokines CX(3)CL1 and CXCL16 with their respective receptors CX(3)CR1 and CXCR6 in the recruitment of T cell and monocyte subsets and shear-mediated plaque modulation will be discussed. Finally, the role of CXCR2 and CXCR4, their respective ligands CXCL1 and CXCL12, and the noncanonical dual agonist MIF in atheroprogression will be dissected. The considerable leap in insight over recent years leads us to anticipate further advances in comprehending the role of chemokines in atherosclerosis, allowing targeted interventions for its prevention and therapy.
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PMID:Chemokines in atherosclerosis: an update. 1856 99

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