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)

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

Interaction between leukocyte and endothelial cells (ECs) is essential for vascular homeostasis and competent immune-inflammatory responses in vivo. Platelet-derived microparticles (PMPs) are generated by high shear stress and may appear in diseased small arteries and arterioles in various clinical settings. In this study, we used flow cytometry and confocal laser scanning microscopy to investigate the effects of high-shear-induced platelet and microparticle activation in adhesion molecules of THP-1 and ECs. We also measured the production of some cytokines and studied cytokine mRNA from THP-1 and ECs after PMP stimulation. PMP stimulation of THP-1 cells increased CD11b, CD32, and CD33 but not CD29, CD31, and CD36. PMP stimulation of ECs increased CD54 and CD63 but not CD9, CD29, and CD31. PMPs induced interleukin-8 (IL-8), interleukin-1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha) production by THP-1. PMPs also induced IL-8, IL-1 beta, and interleukin-6 (IL-6) production by ECs. Production was time-dependent. With RT-PCR, some cytokine mRNAs were detected in THP-1 and ECs after PMP stimulation. In relation to adhesiveness after PMP stimulation, we could clearly observe a shift in distribution not only of CD11b in THP-1 cells but also of CD54 in ECs. In addition, anti-P-selectin glycoprotein ligand-1 antibody reduced the expression of CD11b, CD32, and CD33 in THP-1 after PMP stimulation. These results suggest that high-shear-induced microparticles may contribute to the development of atherosclerosis and participate in vascular damage in inflammatory disorders.
Atherosclerosis 2001 Oct
PMID:High-shear-stress-induced activation of platelets and microparticles enhances expression of cell adhesion molecules in THP-1 and endothelial cells. 1158 5

Inflammation plays an important role in the pathogenesis of atherosclerosis and acute coronary syndromes. Cytokines IL-10 and TNF-alpha exert opposite functions in inflammatory reactions, IL-10 acting predominantly as an antiinflammatory and TNF-alpha as a proinflammatory factor. Functional single nucleotide polymorphisms in the genes of IL-10, TNF-alpha, and TNF-beta are associated with gene expression and plasma levels of IL-10 and TNF-alpha. The aim of the study was to assess whether these IL-10 and TNF gene polymorphisms are related to the risk of coronary artery disease (CAD) and myocardial infarction (MI). Consecutive, angiographically examined patients with significant coronary stenoses but without symptoms or signs of old or acute MI constituted the group with CAD (n=998) and patients with old or acute MI constituted the group with MI (n=793). Subjects with neither angiographic CAD nor symptoms or signs of MI (n=340) served as controls. They were matched with the patients for age and sex. Genotyping was performed with techniques based on the polymerase chain reaction. Allele frequencies, genotype distributions, and frequencies of allele combinations for three IL-10 promoter polymorphisms, -1082G/A, -819C/T and -592C/A, were similar between CAD patients, MI patients, and matched controls. Similarly, genetic analysis did not reveal group-specific differences for the TNF-alpha promoter polymorphisms -863C/A and -308G/A, as well as for the TNF-beta intron 1 polymorphism 252G/A. In addition, no relationship was found between specific combinations of IL-10 and TNF alleles, indicative of low IL-10 and high TNF-alpha production, respectively, and CAD or MI. The lack of association persisted also after adjusting for other cardiovascular risk factors. Our findings suggest that six different and functionally relevant polymorphisms of the genes coding for IL-10, TNF-alpha, and TNF-beta are neither separately nor in cooperation associated with the risk of CAD or MI in angiographically examined patients.
Atherosclerosis 2001 Nov
PMID:Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction. 1168 15

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

One hallmark of inflammation is the proliferation of bystander cells such as vascular smooth muscle cells (SMC), a process governed by growth factors and cytokines. Whereas cytokine induction of gene products promoting inflammation and proliferation is well characterized, little is known about the concomitant down-regulation of potentially counter-regulatory gene products in these cells. By employing the suppression subtractive hybridization-PCR technique, RNA isolated from rat aortic SMC treated with the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) was subtracted from RNA of control cells. Eleven genes were identified, the expression of which fell by 44-77%. One, the transcriptional repressor splicing factor-1 or zfm1, was characterized further. Antisense oligonucleotide suppression of zfm1 protein synthesis mimicked the stimulatory effects of IL-1 beta and TNF alpha on SMC proliferation and expression of the chemokine MCP-1 and the vascular cell adhesion molecule-1. Moreover, in an in vivo mouse model of atherosclerosis, zfm1 abundance was decreased in proliferating arterial SMC. These findings suggest a role for zfm1 in controlling both proliferation and expression of pro-inflammatory gene products in SMC. Therefore, cytokine-induced down-regulation of zfm1 expression may contribute to the pathogenesis of hyperproliferative inflammatory diseases.
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PMID:Cytokine-induced down-regulation of zfm1/splicing factor-1 promotes smooth muscle cell proliferation. 1174 20

Interleukin-1 (IL-1) is a key mediator in the cytokine network, controlling important functions in the immune system, during development, infection, inflammation, cell-differentiation, tissue remodelling, and even cell death. The agonistic isoforms of IL-1 (i.e., IL-1alpha and IL-1beta), the IL-1 receptor antagonists, the receptors and receptor-associated proteins, as well as the recently identified IL-18 and its receptor belong to the IL-1 family of proteins. Activation of the IL-1beta and IL-18 precursors is performed enzymatically by caspase-1, previously termed IL-1beta-converting enzyme (ICE). This molecule is the founding member of the caspase family of enzymes, which are involved in maturation of cytokines and in initiation and execution of apoptotic processes. It has been suggested that cytokines and apoptosis are involved in pathogenesis of cardiovascular diseases such as atherosclerosis, chronic heart failure, myocarditis, cardiomyopathy, or stroke. Since IL-1, like TNF, is a central mediator in the cytokine network, it may act as a potent activator of cardiovascular cells. We know that cells of the vessel wall and the heart can produce IL-1 and respond to this mediator by production of other cytokines or regulation of other cardiovascular cell functions. Thus, this report summarizes general information about the molecules of the IL-1 family of proteins, including the caspases, as well as data regarding these proteins in relation to the vessel wall and the heart and their role in cardiovascular disease in adults and children. The summarized information indicates a role of these molecules in regulation of local inflammatory responses during cardiovascular disease.
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PMID:Interleukin-1 and related proteins in cardiovascular disease in adults and children. 1177 30

Like in many other cell types, apoptosis can be induced by different stress in cells isolated from the cardiovascular system. The mitochondrial apoptotic pathway can be activated by serum deprivation, (9, 66) staurosporine treatment, (110) and oxidative stress. (14) The cytokine pathway is activated by TNF or Fas. (43, 52, 107) Immunohistochemical analysis of endomyocardial biopsies from patients with congestive heart failure, acute myocardial infarction, ischemic cardiomyopathies, and myocarditis, have led to the identification of apoptotic cardiomyocytes. (15 41, 74) Therefore, the pre-existing death program evidenced in isolated cardiomyocytes also may be activated in cardiomyopathies. Apoptosis also has been detected in vascular diseases, such as atherosclerosis, hypertension, and restenosis.49 It is likely that mitochondria, through permeabilization of their outer membrane, play a major role in many apoptotic responses leading to cardiomyocyte apoptosis. Elucidation of the mechanism whereby mitochondrial cell-death effectors are released in the cytosol should open the opportunity of developing compounds able to regulate the progression of apoptosis. The development of drugs acting on the mitochondrion may allow the prevention or the limitation of the seriousness of many cardiovascular diseases in which apoptosis has been detected.
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PMID:Involvement of mitochondria in apoptosis. 1178 13

Inflammatory processes are involved with all phases of atherosclerotic lesion growth. Tumor necrosis factor-alpha (TNFalpha) is an inflammatory cytokine that is thought to contribute to lesion development. Lymphotoxin-alpha (LTalpha) is also a proinflammatory cytokine with homology to TNFalpha. However, its presence or function in lesion development has not been investigated. To study the role of these molecules in atherosclerosis, the expression of these cytokines in atherosclerotic lesions was examined. The presence of both cytokines was observed within aortic sinus fatty streak lesions. To determine the function of these molecules in regulating lesion growth, mice deficient for TNFalpha or LTalpha were examined for induction of atherosclerosis. Surprisingly, loss of TNFalpha did not alter lesion development compared with wild-type mice. This brings doubt to the generally held concept that TNFalpha is a "proatherogenic cytokine." However, LTalpha deficiency resulted in a 62% reduction in lesion size. This demonstrates an unexpected role for LTalpha in promoting lesion growth. The presence of LTalpha was observed in aortic sinus lesions suggesting a direct role of LTalpha in modulating lesion growth. To determine which receptor mediated these responses, diet-induced atherosclerosis in mice deficient for each of the TNF receptors, termed p55 and p75, was examined. Results demonstrated that loss of p55 resulted in increased lesion development, but loss of p75 did not alter lesion size. The disparity in results between ligand- and receptor-deficient mice suggests there are undefined members of the TNF ligand and receptor signaling pathway involved with regulating atherogenesis.
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PMID:Loss of lymphotoxin-alpha but not tumor necrosis factor-alpha reduces atherosclerosis in mice. 1180 56

There is accumulating evidence for a role of tumor necrosis factor-alpha (TNF-alpha) in insulin resistance induced by obesity. The purpose of this study was to investigate whether the TNF alpha/G-308A polymorphism was associated with responses to oral glucose and fat tolerance tests in a case--control study comparing male offspring with a paternal history of premature myocardial infarction (cases, n=335) to age-matched controls (n=340) recruited from 14 European university populations. Genotype frequencies did not significantly differ between cases and controls. Among cases, those carrying the A allele exhibited a higher area under the curve for insulin (64.5 vs 55.9 mU h/l, P=0.009), a higher increment between baseline concentration and peak of insulin (63.1 vs 52.8 mU/l, P=0.005) and a greater decrease between peak and insulin at 120 min (49.1 vs 36.8 mU/l, P=0.003) than those with the GG genotype. No such effect was observed in control subjects. No association was observed with response to a fat tolerance test either in cases or in controls. The present results suggest that the TNF alpha/G-308A polymorphism might interact with other susceptibility factors to coronary heart disease to predispose to insulin resistance, and that the ability of TNF-alpha to induce insulin resistance may extend beyond obesity.
Atherosclerosis 2002 Apr
PMID:The TNF alpha/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease: the European Atherosclerosis Research Study II. 1188 14

Background: Cytokines may play a role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). Methods: We examined serum concentrations of selected pro- (TNFalpha, IL-2) and anti-inflammatory (IL-10) cytokines, and soluble forms of TNF receptors (sTNFR 1 and sTNFR 2) by ELISA in 45 patients with stable exertional angina (group 1), 32 patients with unstable angina (group 2), and 20 healthy subjects (group C). Results: Serum concentrations of both TNFalpha (group 1, 18.3; group 2, 17.2 pg/ml; P<0.001) and IL-10 (group 1, 46.1; group 2, 41.5 pg/ml; P<0.05) were significantly higher in patients with CAD than in group C (8.3 and 14.3 pg/ml, respectively). sTNFR 1 serum level was higher in group 1 (1399.6; P<0.05) than in healthy volunteers (1093.9 pg/ml). In turn, the serum level of IL-2 was significantly higher in unstable patients than it was in groups 1 and C (89.4, 59.8 and 52.8 pg/ml, respectively). In group 1, both TNFalpha and IL-2 correlated with serum lipids. Conclusions: Patients with CAD, irrespective of the form of the disease, have higher serum levels of pro- and anti-inflammatory cytokines than control subjects. Increased concentrations of IL-2 in unstable angina may suggest additional immunologic activation. The pro-inflammatory cytokine levels seem to be related to lipid disturbances.
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PMID:Selected cytokines and soluble forms of cytokine receptors in coronary artery disease. 1189 69


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