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)

Infection with Chlamydia pneumoniae has been implicated as a potential risk factor for atherosclerosis. This study demonstrated the effects of gamma interferon (IFN-gamma)-mediated indoleamine 2,3-dioxygenase activity on C. pneumoniae persistence in HEp-2 cells, inclusion morphology, and ultrastructure. C. pneumoniae replication showed a dose-dependent decrease when treated with increasing concentrations of IFN-gamma and a phenotypic switch resulting in a decrease in typical inclusions with an increase in smaller, less-dense atypical inclusions. Ultrastructural analysis of IFN-gamma-treated C. pneumoniae revealed atypical inclusions containing large reticulatate-like aberrant bodies with no evidence of redifferentiation into elementary bodies.
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PMID:Characterization of Chlamydia pneumoniae persistence in HEp-2 cells treated with gamma interferon. 1170 79

Intimal proliferation of smooth muscle cells (SMCs) is a key event in the vascular response to injury, including the early stages of atherosclerosis and restenosis after angioplasty. Tumor necrosis factor-alpha (TNF-alpha) has been reported to stimulate growth of cultured human SMCs, but activation of TNF receptors is also known to induce cell death by apoptosis. We report here that SMCs isolated from the neointima of injured rat aortas are characterized by increased expression of TNF-alpha in response to interleukin-1beta and gamma-interferon compared with medial SMCs. Basal and serum-stimulated DNA synthesis was higher in intimal than in medial SMCs. In contrast to previous findings on human SMCs, exposure to interleukin-1beta/gamma-interferon or TNF-alpha did not affect the growth of rat medial SMCs, inhibited DNA synthesis, and decreased cell numbers in cultures of intimal SMCs. Incubation of intimal SMCs with these cytokines also resulted in induction of terminal dUTP nick end-labeling positivity and caspase-3 expression, suggesting cell death by apoptosis, whereas medial cells were markedly less sensitive in this respect. Cytokine-induced apoptosis in intimal cells was effectively inhibited by treatment with antibodies against TNF receptors. These findings suggest that endogenous activation of TNF receptors may represent a way to limit accumulation of SMCs in injured arteries. This mechanism may also be important in SMC death in advanced atherosclerotic plaques.
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PMID:Increased rate of apoptosis in intimal arterial smooth muscle cells through endogenous activation of TNF receptors. 1174 63

Clinical studies have suggested a causal or contributory role of Chlamydia pneumoniae infection in asthma and atherosclerosis. The activation of synthetic functions of smooth muscle cells (SMC) including the production of cytokines and growth factors plays a major role in the formation of fibrous atherosclerotic plaques as well as in structural remodelling of the airway wall in chronic asthma. In this study we demonstrated that C. pneumoniae induced the production of low levels of interferon (IFN)-beta in bronchial and vascular SMC when infected cells were treated with tumour necrosis factor-alpha (TNF-alpha). IFN-beta production was analysed by reverse transcription-PCR and enzyme-linked immunosorbent assay. The upregulation of IFN-beta was paralleled by an increase in mRNA levels of interferon regulatory factor-1 and interferon-stimulated gene factor 3gamma, two transcription factors activating the expression of the IFN-beta gene. In addition, C. pneumoniae infection enhanced the mRNA level of indoleamine 2,3-dioxygenase, an IFN-inducible factor mediating the restriction of intracellular chlamydial growth, in TNF-alpha-stimulated SMC. C. pneumoniae-induced IFN-beta production by SMC may modulate inflammation and tissue remodelling during respiratory and vascular infection.
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PMID:Interferon-beta induction by Chlamydia pneumoniae in human smooth muscle cells. 1175 Feb 16

Persistent infections with Chlamydia pneumoniae have been implicated in the development of chronic diseases, such as atherosclerosis and asthma. Although azithromycin, clarithromycin, and levofloxacin are frequently used for the treatment of respiratory C. pneumoniae infections, little is known about the dose and duration of therapy needed to treat a putative chronic C. pneumoniae infection. In this study, we investigated the effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on the viability of C. pneumoniae and cytokine production in an in vitro model of continuous infection. We found that a 30-day treatment with azithromycin, clarithromycin, and levofloxacin at concentrations comparable to those achieved in the pulmonary epithelial lining fluid reduced but did not eliminate C. pneumoniae in continuously infected HEp-2 cells. All three antibiotics decreased levels of interleukin-6 (IL-6) and IL-8 in HEp-2 cells, but this effect appeared to be secondary to the antichlamydial activity, as the cytokine levels correlated with the concentrations of microorganisms. The levels of IL-1beta, IL-4, IL-10, tumor necrosis factor alpha, and gamma interferon were too low to assess the effect of antibiotics. These data suggest that the dosage and duration of antibiotic therapy currently being used may not be sufficient to eradicate a putative chronic C. pneumoniae infection.
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PMID:Effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on Chlamydia pneumoniae in a continuous-infection Model. 1179 50

Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-gamma, represent a critical step in atherogenesis and arteriosclerosis. IFNgamma pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNgamma signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARalpha and PPARgamma mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNgamma protein secretion from 0 to 504+/-168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARalpha (WY14643 or fenofibrate) or PPARgamma (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNgamma secretion in a concentration-dependent manner. PPAR activators also inhibited TNFalpha and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARalpha and PPARgamma in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNgamma, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.
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PMID:PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis. 1193 39

Research during the last two decades established atheromatous lesions as active sites of inflammation and immune responses, contrasting to the traditional view of atherosclerosis as an acellular lesion composed of lipid deposits. In particular, cytokines appear to orchestrate the chronic development of atherosclerosis, eventually leading to the formation of complex atherosclerotic plaques, which can trigger acute thromboembolic complications, such as myocardial infarction or stroke. Indeed the rupture-prone plaque, characterized by a thin fibrous cap overlaying a voluminous lipid core, exhibits accumulation of various pro-inflammatory cytokines. These cytokines may control the clinical consequences of plaques by mediating infiltration and accumulation of immunocompetent cells, directing the turnover of fibrillar collagens (governing the fragility of the fibrous cap), or enhancing foam cell formation and thrombogenicity of the lipid core, among other processes outlined in this review. Thus, understanding the role of cytokines in the pathophysiology of the atherosclerotic plaque might provide a promising therapeutic avenue for this prevalent human disease. This review will focus on members of the interleukin, tumor necrosis factor, and interferon families of cytokines in modulating key processes of atherogenesis.
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PMID:Cytokines in the pathogenesis of atherosclerosis. 1236 24

We analyzed the concentrations of interleukins (IL)-6, IL-10, IL-12, and IL-18, interferon (IFN)-gamma, and high-sensitivity C-reactive protein (hsCRP) in 40 patients with unstable angina (UAP), 39 patients with stable angina (SAP), and 52 age- and gender-matched controls. Compared with the control group, IL-12 concentrations were significantly higher in both the SAP and UAP groups, especially in the UAP group, and the IL-18 concentrations tended to be higher in the UAP group. Conversely, IL-10 concentrations were significantly lower in the SAP and UAP groups. Both IL-6 and hsCRP concentrations were significantly higher in the UAP group. The levels of hsCRP were positively correlated with inflammatory or proinflammatory cytokines (IL-6, IL-12, and IL-18), and negatively correlated with anti-inflammatory cytokine (IL-10). Moreover, the levels of IL-12 were positively correlated with IL-18, and negatively correlated with IL-10, and the results revealed the T-helper 1 dominant state. These results suggested that the inflammatory response was strongly associated with coronary atherosclerosis and angina pectoris, and that the T-helper 1 dominance may play an important role in these diseases.
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PMID:Concentrations of interleukins, interferon, and C-reactive protein in stable and unstable angina pectoris. 1508 94

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis. To study the contribution of angiotensin II in plaque vulnerability, we generated hypertensive hypercholesterolemic ApoE-/- mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE-/- mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE-/- mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE-/- mice had thinner fibrous cap (P<0.01), larger lipid core (P<0.01), and increased macrophage content (P<0.01) than even more hypertensive but normal angiotensin II ApoE-/- mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE-/- mice produced significantly higher amounts of interferon (IFN)-gamma than those from ApoE-/- mice with normal angiotensin II; secretion of IL4 and IL10 was not different. In addition, we provide evidence for a direct stimulating effect of angiotensin II on lymphocyte IFN-gamma production. These findings suggest a new mechanism in plaque vulnerability demonstrating that angiotensin II, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator promoting the induction of vulnerable plaques probably via a T helper switch.
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PMID:Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE-/- mice. 1530 40

Viral and bacterial pathogens have long been suspected to affect atherogenesis directly. However, mechanisms linking innate immunity to chronic inflammatory diseases such as atherosclerosis are still poorly defined. Here we show that infection of primary human aortic smooth muscle cells (HAOSMC) with human cytomegalovirus (HCMV) leads to activation of the novel IkappaB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), a major effector of the cellular innate immune response. We demonstrate that part of the HCMV inflammatory response is most likely mediated via this novel kinase because the canonical IKK complex was only poorly activated upon infection of HAOSMC. An increase in TBK1 phosphotransferase activity led to a strong activation of the interferon regulatory factor (IRF)-3 transcription factor as measured by its C-terminal phosphorylation, dimerization, and DNA binding activity. In addition to TBK1, HAOSMC also express another IKK-related kinase isoform, IKKepsilon, albeit at a lower level. Nevertheless, both isoforms were required for full activation of IRF-3 by HCMV. The transcripts of proatherosclerotic genes Ccl5 (encoding for the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted)) and Cxcl10 (encoding for the chemokine IP-10 (interferon-gamma-inducible protein 10)) were induced in an IRF-3-dependent manner after HCMV infection of smooth muscle cells. In addition, cytokine arrays analysis showed that RANTES and IP-10 were the predominant chemokines present in the supernatant of HCMV-infected HAOSMC. Activation of the TBK1/IRF-3 pathway was independent of epidermal growth factor receptor and pertussis toxin-sensitive G protein-coupled receptor activation. Our results thus add additional molecular clues to a possible role of HCMV as a modulator of atherogenesis through the induction of a proinflammatory response that is, in part, dependent of an IKK-related kinase pathway.
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PMID:Roles of an IkappaB kinase-related pathway in human cytomegalovirus-infected vascular smooth muscle cells: a molecular link in pathogen-induced proatherosclerotic conditions. 1561 5


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