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)

Increased expression of secretory non-pancreatic phospholipase A(2) (sPLA(2)-IIA) could be part of the inflammatory reaction in atherosclerosis. However, the factors controlling sPLA(2)-IIA production in human vascular cells are unknown. We investigated regulation of sPLA(2)-IIA expression and secretion by human arterial smooth muscle cells in culture (HASMC). SPLA(2)-IIA was induced after 3-14 days of culture in non-proliferating conditions. SPLA(2)-IIA was co-expressed with heavy caldesmon, a cytoskeleton protein, and p27, a G(1) cyclin inhibitor, proteins characteristically expressed by differentiated cells. Further incubation with 50-500 units/ml of interferon (IFN)-gamma significantly increased sPLA(2)-IIA mRNA and secretion. IFN-gamma-induced sPLA(2)-IIA was found to be active in cell media and associated with cell membrane proteoglycans. IFN-gamma induced sPLA(2)-IIA expression was antagonized by tumor necrosis factor (TNF)-alpha and interleukin (IL)-10. TNF-alpha added individually induced a significant but transient (4 h) increase in sPLA(2)-IIA secretion. IL-10 by itself did not affect sPLA(2)-IIA expression and secretion. IFN-gamma-stimulated sPLA(2)-IIA transcription involved STAT-3 protein. Interestingly, IL-6 but not IFN-gamma up-regulated the sPLA(2)-IIA expression in HepG2 cells, thus sPLA(2)-IIA induction by IFN-gamma response appears to be cell specific. In summary, conditions leading to cell differentiation induced sPLA(2)-IIA expression in HASMC and further exposure to IFN-gamma can up-regulate sPLA(2)-IIA transcription and secretion. This IFN-gamma stimulatory effect can be modulated by other cytokines.
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PMID:Interferon-gamma induces secretory group IIA phospholipase A2 in human arterial smooth muscle cells. Involvement of cell differentiation, STAT-3 activation, and modulation by other cytokines. 1081 52

Hydroxymethylglutaryl CoA (HMG CoA) reductase inhibitors, or statins, have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. Atherosclerotic plaque lesions can be chronically inflamed and vulnerable to rupture or stable and less rupture-prone. Human smooth muscle cells (SMC) are critically important in maintaining the stability of atherosclerotic plaques. This stability may be greatly influenced by pro-inflammatory mediators such as IFN-gamma, TNF-alpha, and Il-1beta and Fas ligand (FasL) that are present in human atheroma. The purpose of the present study was to examine the effect of the statins on apoptosis of SMC. We have found that SMC are normally resistant to Fas or cytokine-induced apoptosis, but can be sensitized to these agents with pharmacological concentrations of some statins. Simvastatin and lovastatin strongly sensitized the cells to apoptotic agents while atorvastatin was less effective. In contrast to the lipophilic statins, the hydrophilic statin pravastatin did not induce this sensitization of SMC to apoptosis. Treatment of SMC with either mevalonate, the product of the HMG-CoA reductase, or geranylgeranylpyrophosphate, a down stream intermediate, prevented lipophilic statin-induced sensitization to apoptosis. These results suggest that prenylation of one or more proteins is critically involved in regulating the sensitivity of SMC to apoptotic stimuli. Our data support the emerging evidence that through this pathway the various statins may have effects which are beyond a simple lowering of the levels of circulating cholesterol.
Atherosclerosis 2000 Sep
PMID:Inhibitors of HMG-CoA reductase sensitize human smooth muscle cells to Fas-ligand and cytokine-induced cell death. 1099 58

Infection with Chlamydia pneumoniae, a human respiratory pathogen, has been implicated as a potential risk factor in atherosclerosis, possibly because the pathogen can exist in a persistent form similar to that described for Chlamydia trachomatis. The present study investigated whether gamma interferon (IFN-gamma) can induce indoleamine 2,3-dioxygenase (IDO) activity in aortic smooth muscle cells, leading to a marked inhibition of C. pneumoniae growth. Our data indicate a stimulation of IDO mRNA expression and dose-dependent enzymatic activity following IFN-gamma treatment. IDO-mediated increase in tryptophan catabolism resulted in a dose-dependent marked inhibition of C. pneumoniae replication.
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PMID:Inhibition of Chlamydia pneumoniae replication in human aortic smooth muscle cells by gamma interferon-induced indoleamine 2, 3-dioxygenase activity. 1103 63

Systemic inflammation, represented in large part by the production of pro-inflammatory cytokines, is the response of humans to the assault of the non-self on the organism. Three distinct types of human ailments - namely autoimmunity, presenile dementia (Alzheimer's disease), or atherosclerosis - are initiated or worsened by systemic inflammation. Autoimmunity is unregulated hyperimmunity to organ-specific proteins, inducing rapid turnover of antigen-specific T cells of the acquired immune system with ultimate exhaustion and loss of acquired immunity IL-2 and IFN-gamma production and proliferative decline, conforming to the limited capacity of clonal division (Hayflick phenonmenon). In Alzheimer's disease (AD), the primary degenerative process of amyloid-beta (AJ3) protein precedes a cascade of events that ultimately leads to a local "brain inflammatory response". Unregulated systemic immune processes are secondary but important as a driving-force role in AD pathogenesis. Atherosclerosis, an underlying cause of myocardial infarction, stroke, and other cardiovascular diseases, consists of focal plaques characterized by cholesterol deposition, fibrosis, and inflammation. The presence of activated T lymphocytes and macrophages indicate a local immunologic activation in the atherosclerotic plaque that may be secondary to unregulated pro-inflammatory cytokines too. The premature hyperimmunity of autoimmunity, the local "brain inflammatory response" to A/3 protein in AD, and the immune response to fatty changes in vessels in atherosclerosis all signal the critical importance of unregulated systemic inflammation to common neurological and cardiovascular disease that shortens the nominal longevity of humans.
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PMID:Unregulated inflammation shortens human functional longevity. 1113 Dec 95

In addition to established factors such as hyperlipidemia, smoking and hypertension, inflammation and infection have recently been implicated as major risk factors for atherosclerotic disease. Proatherogenic effects induced by infection may be related to both systemic inflammation and to direct effects on the vascular wall. We report here that a high fat diet combined with a protozoal infection with known tropism to the heart induced early atherosclerosis and intimal inflammatory infiltrates (CD4+, CD8+ cells and macrophages) in aortas of all (n = 7) CBA/J mice investigated. These mice are normally quite resistant to atherosclerotic development and in the control group (n = 7) receiving only a fatty diet, only one mouse presented a lesion. This lesion was completely devoid of infiltrating CD8+ cells. Parasite-infected mice receiving a normal diet exhibited vasculitis, but no signs of atherosclerosis and control mice receiving normal diet, as expected, exhibited neither signs of vasculitis nor atherosclerosis. Secretion of IL-6, TNF-alpha, and IFN-gamma were demonstrated in all atherosclerotic lesions and IL-6 appeared to be the dominant cytokine, both in the lesions themselves as well as in the intimal-medial junction. There were no traces of parasites present in the artery wall, indicating that atherosclerosis was induced via an indirect route. We conclude that a high fat diet in conjunction with infection and systemic (or localized) inflammation may have a strong proatherogenic effect. Finally, we suggest that CBA/J mice infected with T. cruzi parasites and given a fatty diet could serve as a useful experimental model in the continued analysis of factors contributing to the induction of atherosclerosis.
Atherosclerosis 2000 Dec
PMID:Induction of early atherosclerosis in CBA/J mice by combination of Trypanosoma cruzi infection and a high cholesterol diet. 1116 16

The immune system has to be optimally balanced to be highly effective against infections with cytopathic microbial pathogens and must guarantee efficient destruction of cells infected with noncytopathic agents while leaving the integrity of noninfected cells largely unaltered. We describe here the effects of genetically induced hypercholesterolemia on cellular immunity in apolipoprotein E (ApoE(-/-)) and low density lipoprotein receptor-deficient (LDLR(-/-)) mice during infection with the hepatotropic lymphocytic choriomeningitis virus WE strain. In both ApoE(-/-) and LDLR(-/-) mice hypercholesterolemia aggravated virus-induced immunopathologic liver disease. ApoE(-/-) mice exhibited a higher susceptibility to virus-induced immunopathology than LDLR(-/-) mice and usually succumbed to immunopathologic disease when infected with high doses of virus. Initial virus spread was not influenced by the hypercholesterolemia, whereas clearance of the virus from spleen and nonlymphoid organs, including liver, was delayed. Activation of antiviral CTL, measured by ex vivo cytotoxicity and IFN-gamma production, and recruitment of specific CTL into blood and liver were impaired in hypercholesterolemic mice, indicating that hypercholesterolemia had a significant suppressive effect on cellular immunity. Taken together, these data provide evidence that hypercholesterolemia suppresses antiviral immune responses, thereby changing the host-virus balance, and can increase susceptibility to acute or chronic and potentially lethal virus-induced immunopathologic disease. These findings impinge on our understanding of hypercholesterolemia as a disease parameter and may explain aspects of the frequent association of persistent pathogens with hypercholesterolemia-induced diseases, such as atherosclerosis.
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PMID:Hypercholesterolemia exacerbates virus-induced immunopathologic liver disease via suppression of antiviral cytotoxic T cell responses. 1120 93

Vascular endothelium is an important site for a wide array of immunological processes such as inflammation, atherosclerosis and allograft rejection. Culture methods of mouse vascular endothelium would provide an important in vitro correlate to immunological murine in vivo models. We describe a simple method to culture mouse vascular endothelium from thoracic aorta. Our cultured cells express typical phenotypic (CD105, CD31, CD106), morphological and ultrastructural (intercellular junctions, Weibel-Palade bodies) markers of vascular endothelium. They also possess functional receptors for uptake and processing of acetylated low-density lipoproteins. The mouse vascular endothelium within our system expresses high levels of MHC class I and MHC class II after activation with IFN-gamma. In addition, these cells express the accessory molecules CD80 and CD54, while they lack constitutive expression of CD86 and CD40, providing them the means to function as antigen presenting cells. Alloreactive CD4(+) and CD8(+) T lymphocytes demonstrate evidence of DNA synthesis after co-culture with activated vascular endothelium indicating their commitment to proliferation. In conclusion, we describe a simple culture system to isolate and grow mouse vascular endothelium, which provides a powerful tool to study biological interactions in vitro.
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PMID:A simple method for culturing mouse vascular endothelium. 1140 51

Endothelial activation is an important feature of many inflammatory diseases and has been implicated as the cause of vascular complications in disorders such as diabetes, atherosclerosis, and transplant rejection. One of the most potent activators of the endothelium is TNF, which can also be expressed by endothelial cells, causing a permanent, autocrine stimulatory signal. To establish a model of continuous endothelial activation and to elucidate the role of endothelial derived TNF in vivo, we generated transgenic mice expressing a noncleavable transmembrane form of TNF under the control of the endothelial-specific tie2 promoter. Adult tie2-transmembrane TNF-transgenic mice developed chronic inflammatory pathology in kidney and liver, characterized by perivascular infiltration of mononuclear cells into these organs. Along with the infiltrate, an up-regulation of the adhesion molecules ICAM-1 and VCAM-1, but not E-selectin, in the endothelium was observed. Despite predisposition to chronic inflammation these mice were protected from immune-mediated liver injury in a model of Con A-induced acute hepatitis. Although the blood levels of soluble TNF and IFN-gamma were increased in transgenic animals after challenge with Con A, no damage of hepatocytes could be detected, as assessed by the lack of increase in plasma transaminase activities and the absence of TUNEL staining in the liver. We conclude that expression of transmembrane TNF in the endothelium causes continuous endothelial activation, leading to both proinflammatory and protective events.
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PMID:Chronic inflammation and protection from acute hepatitis in transgenic mice expressing TNF in endothelial cells. 1156 13

With emphasis on the pulmonary circulation, three general types of vascular disease are discussed: fibroproliferative (atherosclerosis), cellular proliferative (endothelial neoplasms) and inflammatory (granulomatous vasculitis). The causes of these phenotypic responses are invariably multifactorial, but infectious agents including viruses, Chlamydia, Helicobacter, Rickettsia, mycobacteria and other infectious agents have been increasingly implicated in the pathophysiology. The classifications of vascular diseases are complicated and confusing and many eponymous diseases are specific variations of more general disease processes. The pivotal role of the monocyte/macrophage and T-cells is discussed, particularly with regard to intracellular infections. In addition to antimicrobial therapy, modifications of macrophage function by IFN-gamma and blockade of TNF are attractive areas for therapeutic research. Diseases with many synergistic causes will probably also require multifaceted therapeutic interventions.
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PMID:The role of infectious agents in pulmonary and systemic vascular disease. 1158 60

Inflammatory mechanisms appear to influence the progression of intimal thickening in experimental models of arterial injury. Intravenous immunoglobulin (IVIG) is a polyspecific preparation of human immunoglobulin (Ig)G employed for treatment of autoimmune disorders. In this study, we sought to investigate whether treatment with IVIG could influence intimal thickening in a model of murine arterial injury. Intimal thickening was induced by placement of a periadventitial cuff over the right femoral artery of male C57BL/6 mice. In the first experiment, IVIG or human serum albumin (HSA) (10 mg/mouse) were administered intraperitoneally for five consecutive days starting 1 day prior to cuff placement. In the second experiment, IVIG or HSA treatment were delivered similarly, but initiated 3 days following induction of arterial injury. Neointimal area and intimal/medial ratio were significantly reduced in mice treated with IVIG prior to cuff placement as compared with HSA treatment. No differences were noted with regard to neointimal area or intimal/medial ratio, between IVIG- and HSA-treated mice when the treatment was commenced 3 days following induction of injury. IVIG treatment reduced the proliferative capacity of splenocytes to the non-specific mitogen Con-A. Treatment with IVIG was associated with a significantly enhanced secretion of interleukin (IL)-10) by the respective splenocytes in comparison with HSA-treated mice. No effect of IVIG was evident on the secretion of IL-4 or IFN-gamma. Thus, IVIG has proven beneficial in ameliorating intimal thickening in a mouse model of arterial injury. The effect could be mediated by upregulation of T-cell secretion of the anti-inflammatory cytokine IL-10.
Atherosclerosis 2001 Nov
PMID:The effect of intravenous immunoglobulins on intimal thickening in a mouse model of arterial injury. 1168 9


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