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)

Excessive dietary fat and cholesterol exacerbate atherosclerosis. To obtain unbiased insight into the early pathological changes induced by fat feeding in the artery wall, we used high-density microarrays to generate transcriptional profiles of aortic tissue from two groups of atherosclerosis-prone apolipoprotein E-null mice: controls maintained on standard chow and experimental animals exposed short-term to a Western-type diet, a regimen which produced severe hypercholesterolemia without significant development of atheromas. By applying rigorous selection criteria, we identified 311 genes differentially regulated by these dietary conditions. The set of diet-regulated genes exhibited striking functional relationships and represented both novel and known regulatory networks implicated in injury of the artery wall, including cell adhesion genes, histocompatibility antigen and major histocompatibility complex genes, flavin-containing monooxygenases, interferon-regulated genes, small inducible cytokines, collagen and procollagen genes, and complement system components. Further examination of genes identified by this study will provide insights into the molecular mechanisms by which high-fat cholesterol-rich dietary regime initiates pathological alterations in healthy arteries.
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PMID:Transcriptional profiling of early onset diet-induced atherosclerosis in apolipoprotein E-deficient mice. 1576 75

Hepatic steatosis is the hallmark of nonalcoholic fatty liver disease (NAFLD), which is the consequence of multiple metabolic derangements among which insulin resistance plays a pivotal role. Steatosis is, also, a feature of hepatitis C virus (HCV) infection. However, in chronic hepatitis C, the prevalence of steatosis is 2.5-fold more elevated than that expected by a chance concurrence with NAFLD, suggesting that HCV may be implied in the development of steatosis. As observed in NAFLD, in patients infected with HCV genotype 1 steatosis is associated with an increased body mass index. On the other hand, in patients infected with genotype 3 the extent of steatosis strictly correlates with the viral load indicating that steatosis is mainly "virus-related". Regardless of the "metabolic" or "viral" etiology, hepatic steatosis in HCV contributes to the progression of liver fibrosis, to the development of hepatocellular carcinoma and to an impaired response to interferon treatment. Features such as obesity, insulin resistance and type 2 diabetes mellitus are shared by NAFLD and HCV-associated steatosis. In addition, HCV infection, directly or through steatosis, favors the development of type 2 diabetes mellitus. Hyperlipidemia is an independent predictor of the development of NAFLD, but not of HCV-associated steatosis. Arterial hypertension is common in nonalcoholic steatohepatitis patients, and HCV infection has recently been acknowledged as an independent risk factor for atherosclerosis. The role of iron in the progression of both NAFLD and HCV-associated steatosis remains controversial while lipoperoxidation and oxidative stress are pathogenic mechanisms shared by both. Some metabolic risk factors may be shared by both HCV-associated steatosis and NAFLD although the disease progression and pathophysiological background may be different. Preliminary data suggest that the therapeutic options for NAFLD may also be useful to improve HCV-associated steatosis.
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PMID:[Hepatitis C virus-associated and metabolic steatosis. Different or overlapping diseases?]. 1585 90

In a recent study, analysis of gene expression in atherectomy specimens derived from restenotic coronary lesions revealed 223 differentially expressed genes. Thirty-seven of these genes indicated activation of interferon- (IFN-) gamma signaling in neointimal smooth muscle cells. Moreover, genetic disruption of IFN-gamma signaling in a mouse model of restenosis significantly reduced the vascular proliferative response. Thus, IFN-gamma is assumed to play an important role in the control of tissue proliferation during neointima formation. We hypothesized that genetic variants of IFN-gamma and its receptor subunits are involved in upregulation of IFN-gamma related genes in neointimal tissue of patients that develop in-stent restenosis. Polymorphisms in the genes encoding for IFN-gamma (IFNG T874A) and its receptors 1 (IFNGR1 C-56T) and 2 (IFNGR2 A839G) were tested for their association with restenosis. IFNG T874A, IFNGR1 C-56T and IFNGR2 A839G genotypes were determined in a consecutive series of patients (n=2591) that had been treated with coronary stents. Follow-up angiography 6 months after stent implantation was performed in 76.8% of the patients. Genotyping was performed with PCR-based methods. IFNG T874A, IFNGR1 C-56T and IFNGR2 A839G genotypes were not associated with the incidence of angiographic and clinical restenosis (P>0.23). Moreover, there was no association between IFNG, IFNGR1 and IFNGR2 genotypes and the combined incidence of death form any cause and non-fatal myocardial infarction during the first 12 months following the intervention (P>0.61). Thus, this study does not support a clinically relevant role of the studied polymorphisms in the processes leading to in-stent restenosis.
Atherosclerosis 2005 Sep
PMID:Interferon-gamma and interferon-gamma receptor 1 and 2 gene polymorphisms and restenosis following coronary stenting. 1611 85

Steatosis is a common feature of chronic hepatitis C, and may be caused directly by the virus, as in genotype 3 infection, or be associated with host metabolic factors. The interaction of hepatitis C virus core protein with the lipoprotein secretion pathways causes the characteristic alterations of lipid metabolism observed in hepatitis C virus-related steatosis. Several pathogenic mechanisms are likely involved into the pathogenesis of hepatitis C virus-related steatosis, including hyper-homocysteinaemia, hypoadiponectinaemia and insulin resistance. Steatosis is a major determinant of the liver damage progression in chronic hepatitis C (CHC), and negatively affects the response rate to the interferon (IFN)-based anti-viral treatment. Moreover, recent evidence suggests that steatosis may contribute to liver carcinogenesis. Chronic hepatitis C is a recognized risk factor for type 2 diabetes and it could be implicated into the pathogenesis of atherosclerosis. The role of hepatitis C virus (HCV)-related steatosis in these epidemiological associations remains to be determined.
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PMID:Review article: hepatitis C virus-associated steatosis--pathogenic mechanisms and clinical implications. 1622 74

Atherosclerosis is a chronic inflammatory disease of the vasculature with lesions developing in the arterial wall, frequently in the coronary and carotid arteries. The interaction between macrophages and lymphocytes within the atherosclerotic lesion microenvironment exemplifies a site where both innate and adaptive immunity contribute towards disease progression. As gamma interferon (IFN-gamma), the classic macrophage activating factor, has been localized to atherosclerotic lesions, this review will focus on its contribution to plaque pathology and will finally consider how current therapies, as exemplified by HMG CoA reductase inhibitors or statins, may impact this process beyond lipid lowering, in part by inhibiting IFN-gamma dependent processes. IFN-gamma sources within the atheroma as well as receptors, signaling pathways and its effects on macrophages as well as on vascular smooth muscle and endothelial cells will be considered. Therapeutic interventions targeting molecular events associated with IFN-gamma signaling offer novel approaches to the treatment of atherosclerosis.
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PMID:Gamma interferon: a central mediator in atherosclerosis. 1628 7

Chronic inflammation in atherosclerosis is responsible for plaque instability through alterations in extracellular matrix. Previously, we demonstrated that major histocompatibility class II (MHC II) transactivator (CIITA) in a complex with regulatory factor for X box 5 (RFX5) is a crucial protein mediating interferon (IFN)-gamma-induced repression of collagen type I gene transcription in fibroblasts. This article demonstrates that, in smooth muscle cells (SMCs), IFN-gamma dramatically increases the expression of CIITA isoforms III and IV, with no increase in expression of CIITA isoform I. Expression of CIITA III and IV correlates with decreased collagen type I and increased MHC II gene expression. Exogenous expression of CIITA I, III, and IV, in transiently transfected SMCs, represses collagen type I promoters (COL1A1 and COL1A2) and activates MHC II promoter. Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-gamma. Moreover, simvastatin lowers the IFN-gamma-induced expression of RFX5 and MHC II in addition to repressing collagen expression. However, simvastatin does not block the IFN-gamma-induced expression of CIITA III and IV, suggesting a CIITA-independent mechanism. This first demonstration that RFX5 and CIITA isoforms are expressed in SMCs after IFN-gamma stimulation suggest that CIITA could be a key factor in plaque stability in atherosclerosis.
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PMID:Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells. 1651 76

Since the discovery of the hepatitis C virus (HCV) in 1989, attention has been paid to the association of chronic HCV infection and the development of diabetes. The risk factors for diabetes include older age, HCV genotype 3, severe liver fibrosis, family history of diabetes, and liver/kidney transplantation. Emerging evidence in animals and humans has shown that HCV infection induces hepatic steatosis and increases tumor necrosis factor-alpha level, both resulting in the development of insulin resistance and subsequent type 2 diabetes. It is suggested that the presence of diabetes and hepatic steatosis may enhance fibrosis progression, hepatocellular carcinoma, and atherosclerosis. Interferon is reportedly associated with improved glucose tolerance. However, interferon might enhance underlying autoimmunity against beta cells, leading to overt type 1 diabetes that is genetically predisposed or give rise to hyperglycemia, resulting in the development of type 2 diabetes. In light of the national epidemic of type 2 diabetes, the link between HCV and diabetes would be a major public health problem. Further clinical researches are awaited in order to effectively detect, prevent, and treat HCV-associated type 2 diabetes, which would also slow the progression of hepatitis C itself.
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PMID:Hepatitis C infection and diabetes. 1650 40

Vascular smooth muscle cell (VSMC) apoptosis occurs in advanced atherosclerotic plaques where it may contribute to plaque instability. VSMCs express the death receptor Fas but are relatively resistant to Fas-induced apoptosis due in part to the intracellular sequestration of Fas. Although inflammatory cytokines such as interferon (IFN)-gamma present in plaques can prime VSMCs to FasL-induced death, the mechanism of this effect is unclear. We examined Fas expression and FasL-induced apoptosis in human VSMCs in response to IFN-gamma. IFN-gamma induced Fas trafficking to the cell surface within 24 hours, an effect that required Jak2/Stat1 activity. IFN-gamma also stimulated Akt activity, and both Fas trafficking and Stat1 activation were inhibited by blocking PI3K, Akt, or Jak-2. IFN-gamma increased Fas-induced apoptosis in vitro by 46 +/- 8% (mean +/- SEM, P = 0.04), an event that could be abrogated by inhibition of PI3K, Akt, or Jak-2. IFN-gamma also increased Fas-induced apoptosis in vivo 7.5- to 15-fold (P < 0.05) in human arteries transplanted into immunodeficient mice, accompanied by increased Fas and phospho-Ser727-Stat1. We conclude that IFN-gamma primes VSMCs to Fas-induced apoptosis, in part by relocation of Fas to the cell surface, a process that involves PI3K, Akt, and Jak-2/Stat1. IFN-gamma present in plaques may co-operate with FasL to induce VSMC apoptosis in atherosclerosis.
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PMID:Interferon-gamma induces Fas trafficking and sensitization to apoptosis in vascular smooth muscle cells via a PI3K- and Akt-dependent mechanism. 1672 18

Hepatitis C Virus is associated with a wide series of extrahepatic manifestations. Based on available data the link between the virus and some of these extrahepatic diseases is only suggested and needs further confirmation. Hepatitis C Virus-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinaemia, represent the most closely related extrahepatic manifestations of Hepatitis C Virus. Other Hepatitis C Virus-associated disorders include nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, porphyria cutanea tarda, lichen planus, diabetes, chronic polyarthritis, cardiopathy and atherosclerosis. A pathogenetic link between Hepatitis C Virus and some extrahepatic manifestations was confirmed by their responsiveness to antiviral therapy, which is now deemed the first therapeutic option to consider. By contrast, there are diseases where treatment with interferon was ineffective or dangerous. The aim of the present paper is to outline the most recent evidence concerning extrahepatic disorders that are possibly associated with Hepatitis C Virus infection. Special emphasis will be given to discussion of the most appropriate clinical approaches to be adopted in order to diagnose, treat (possibly prevent) and follow-up extrahepathic diseases in patients with Hepatitis C Virus infection.
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PMID:Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach. 1845 May 27

Human cytomegalovirus (HCMV) infection appears to be linked to the pathogenesis of atherosclerosis. An association between HCMV infection and an enhanced restenosis rate as well as the induction of vasculopathies after solid organ transplantation has been documented. Knowledge of the cellular and molecular basis of these findings is limited, however. By Northern blot and RT-PCR analysis of human foreskin fibroblasts (HFF) and human coronary artery smooth muscle cells (SMC), we identified extracellular matrix (ECM) genes that were downregulated after HCMV infection, including collagen type I and fibronectin. Quantitative immunoassays showed a significant reduction of soluble collagen type I and fibronectin proteins in supernatants of both cell types. This was shown to be a direct effect of HCMV infection and not due to a response to interferons released from infected cells, since neutralization of alpha and beta interferon activity could not block virus-induced downregulation of matrix proteins. As the amount of ECM depends on both synthesis and degradation, we also assessed the influence of HCMV on the activity of matrix metalloproteinases (MMP). Interestingly, a significant difference in virus-induced matrix degradation could be shown between the two cell types. HCMV upregulated MMP-2 protein and activity in SMC but not in HFF. Thus, HCMV infection of SMC reduces ECM dramatically by inducing two independent mechanisms that influence synthesis as well as degradation of ECM. These may represent molecular mechanisms for HCMV-induced pathogenesis of inflammatory vasculopathies and may facilitate dissemination of HCMV by promoting the detachment of infected cells in vivo.
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PMID:Human cytomegalovirus-induced reduction of extracellular matrix proteins in vascular smooth muscle cell cultures: a pathomechanism in vasculopathies? 1696 42


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