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)

A role for infection and inflammation in atherogenesis is widely accepted. Arterial endothelium has been shown to express heat shock protein 60 (HSP60) and, since human (hHSP60) and bacterial (GroEL) HSP60s are highly conserved, the immune response to bacteria may result in cross-reactivity, leading to endothelial damage and thus contribute to the pathogenesis of atherosclerosis. In this study, GroEL-specific T-cell lines from peripheral blood and GroEL-, hHSP60-, and Porphyromonas gingivalis-specific T-cell lines from atherosclerotic plaques were established and characterized in terms of their cross-reactive proliferative responses, cytokine and chemokine profiles, and T-cell receptor (TCR) Vbeta expression by flow cytometry. The cross-reactivity of several lines was demonstrated. The cytokine profiles of the artery T-cell lines specific for GroEL, hHSP60, and P. gingivalis demonstrated Th2 phenotype predominance in the CD4 subset and Tc0 phenotype predominance in the CD8 subset. A higher proportion of CD4 cells were positive for interferon-inducible protein 10 and RANTES, with low percentages of cells positive for monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha, whereas a high percentage of CD8 cells expressed all four chemokines. Finally, there was overexpression of the TCR Vbeta5.2 family in all lines. These cytokine, chemokine, and Vbeta profiles are similar to those demonstrated previously for P. gingivalis-specific lines established from periodontal disease patients. These results support the hypothesis that in some patients cross-reactivity of the immune response to bacterial HSPs, including those of periodontal pathogens, with arterial endothelial cells expressing hHSP60 may explain the apparent association between atherosclerosis and periodontal infection.
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PMID:Characterization of heat shock protein-specific T cells in atherosclerosis. 1569 20

Toll-like receptor-4 (TLR4) is a pattern-recognition receptor not only for exogenous ligands such as lipopolysaccharide (LPS) of Gram-negative bacteria, but also for endogenous ligands such as fibronectin, heat shock proteins and hyaluronan oligosaccharides. The Asp299Gly allele of the TLR4 gene has been associated with increased risk for severe infections, but reduced progression of atherosclerosis. We have investigated the consequences of the presence of Asp299Gly polymorphism after stimulation of mononuclear cells with lipopolysaccharide (LPS), the non-LPS TLR4 microbial stimuli Aspergillus fumigatus and Cryptococcus neoformans, and the endogenous TLR4 ligand heat shock protein 60. No differences in either production of the proinflammatory cytokine TNF or the antiinflammatory cytokine interleukin-10 were observed between volunteers with the wild-type allele, volunteers heterozygous for the Asp299Gly allele and one volunteer homozygous for the TLR4 variant. In conclusion, the presence of the Asp299Gly TLR4 polymorphism does not result in defective pro and antiinflammatory cytokine production after stimulation with either exogenous (LPS and non-LPS) or endogenous TLR4 ligands, and alternative explanations are likely to be responsible for the epidemiological data showing associations with inflammatory conditions. In addition, this is the first study to demonstrate that even homozygosity for the Asp299Gly mutation does not confer hyporesponsiveness to stimulation with TLR4 stimuli.
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PMID:Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism. 1592 51

The relationship between humoral immunity to hsp60 and type 2 diabetes along with other relevant metabolic, inflammatory and immunogenetic variables was studied in 76 non-diabetic and 74 diabetic persons aged 55-74 years selected from the population-based KORA Survey 2000. Antibodies to human hsp60 were measured in serum samples by ELISA. Hsp60 antibodies were detected in all but two individuals in a considerable range of titres (22-1,856 AU/ml). There was no significant association to age and sex, or to key clinical or metabolic parameters (BMI, WHR, HbA1c, total cholesterol, LDL cholesterol, HDL cholesterol, systolic and diastolic blood pressure, albumin, uric acid) or immunological parameters (CRP, IL-6, sIL-6R, TNFalpha, sTNFalpha R60, sTNFalpha R80). Analysis of antibody-positive individuals revealed an association between hsp60 antibodies and diabetes at borderline significance (p = 0.047), which was lost when the two antibody-negative individuals were included. Genetic analyses indicated that this association was significant in carriers of the C allele of the IL-6 promoter region polymorphism at nucleotide -174 (p = 0.02), but not in GG genotype carriers. We conclude that humoral immunity to human hsp60 may be enhanced in those diabetic patients carrying the -174C allele of the IL-6 gene. This finding may contribute to an understanding of the relationship between the -174C allele and increased risk of atherosclerosis.
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PMID:Association of humoral immunity to human Hsp60 with the IL-6 gene polymorphism C-174G in patients with type 2 diabetes and controls. 1595 88

Chlamydia pneumoniae is a common respiratory tract pathogen, and persistent infections have been associated with atherosclerosis. We studied the effects of repeated chlamydial inoculations on the inflammatory response and on aortic lipid accumulation in C57BL/6J mice. Mice fed a diet supplemented with 0.2% cholesterol were infected three or six times with C. pneumoniae every fourth week. Sera and lungs were analyzed for inflammatory responses, lung tissues were tested for the presence of C. pneumoniae DNA and RNA, and intimal lipid accumulation in the aortic sinus was quantified. High levels of chlamydial heat shock protein 60 (Hsp60) immunoglobulin G2c subclass antibodies were detected in all of the infected mice, and a positive and statistically significant correlation was found between these antibodies and autoantibodies against mouse Hsp60. Both Hsp60 antibody levels correlated with the severity of lung tissue inflammation. The cholesterol supplement in the diet had no effect on serum cholesterol levels. Significantly larger intimal lipid lesions were seen in the mouse group infected six times (6,542 mum(2)) than in the control group (1,376 mum(2); P = 0.034). In conclusion, repeated inoculations increased aortic sinus lipid accumulation in normocholesterolemic mice. The correlation between the antibodies to mouse and chlamydial Hsp60 proteins and their association with lung inflammation further support the theory of the development of an autoimmune response against heat shock proteins after repeated chlamydial infections.
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PMID:Effects of repeated Chlamydia pneumoniae inoculations on aortic lipid accumulation and inflammatory response in C57BL/6J mice. 1617 17

Heart damage, mediated by different autoantibodies can involve several anatomical heart structures: valves, arteries, conduction tissue. Verrucous endocarditis is frequently reported in patients with antiphospholipid syndrome (APS) with or without systemic lupus erythematosus (SLE), particularly if they suffer from central nervous system involvement. Antiphospholipid antibodies (aPL) were shown deposited at subendothelial level of the affected valves. According to several in vitro and in vivo experimental models, aPL, anti-oxidized LDL (oxLDL), anti-heat shock protein 65 (HSP65) and anti-endothelial cells antibodies (AECA) seem to be involved in the pathogenesis of the atherosclerosis phenomena described in systemic autoimmune disease and vasculitis. However, the observation of the association of the same antibodies with clinical and subclinical atherosclerosis in patients is still controversial. The children of anti-Ro/SSA positive mothers can be affected by the congenital heart block. Anti Ro/SS-A antibodies play a major pathogenic role in affecting the heart conduction tissue in this rare condition.
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PMID:Nonorgan specific autoantibodies and heart damage. 1621 61

Atherosclerosis is nowadays generally accepted as an inflammatory disease but the mechanism of its origin and development have not yet been fully clarified. The present review focuses on the role of the local immune system as one of the key players in the pathogenesis of the complex process. Its part represented by vascular-associated lymphoid tissue (VALT) within the arterial wall participates directly in the vascular wall's homeostatis. Its inordinate activation during ontogenic development of an individual, this formerly defensive and physiologic mechanism transform into a pathological process resulting in an impairing inflammation. Hsp60, CRP and oxidized or otherwise modified LDL are serious candidates for triggering these pathological changes. The principal role is played by anti-Hsp60 antibodies and by shear stress originating on the surface of endothelium due to blood flow. The experimental and clinical data supporting this immunological hypothesis of atherosclerosis are discussed.
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PMID:Defects in regulation of local immune responses resulting in atherosclerosis. 1629 29

In recent years, the results of some studies have revealed the possible potential role of several infectious agents in the inflammatory mechanism of atherosclerosis. The detection of specific antibodies against microorganisms such as and as well as Chlamydia pneumoniae and cytomegalovirus as well as antibodies directed to heat shock proteins in the sera of atherosclerotic patients and the presence of genomic material in atheromatous plaques all provide evidence supporting the presumptive role of infectious agents in atherosclerosis. There are some findings that can be accepted as clues for the possible involvement of Mycobacterium tuberculosis in atherosclerosis. These consist of the presence of high levels of mycobacterial heat shock protein 65 in atherosclerotic patients, and in animal studies, the detection of atherosclerotic changes in the vascular wall of animals vaccinated with recombinant heat shock protein 65, and Mycobacterium tuberculosis containing heat shock protein 65. The probable proatherogenic effect of the specific immune response to BCG-associated heat shock protein was also suggested. The mycobacterium cell wall contains a phospholipid, phosphatidylinositol, which was shown to have a procoagulant effect similar to that of a cytomegalovirus possessing phosphatidylserine, another phospholipid showing a procoagulant effect. These data suggest that Mycobacterium tuberculosis may also be involved in the pathogenesis of atherosclerosis.
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PMID:Mycobacterium tuberculosis complex in atherosclerosis. 1641 67

Chlamydia (C.) pneumoniae are thought to infect monocytes and use them as vectors into the vessel wall, where they may accelerate atherosclerosis. We investigated the effects of C. pneumoniae on monocytic matrix metalloproteinase (MMP) activation with focus on the role of the extracellular matrix metalloproteinase inducer EMMPRIN. Human monocytes or monocytic MonoMac6 cells were infected with C. pneumoniae. Infection enhanced mRNA- and surface expression of EMMPRIN and Membrane-type-1 Matrix Metalloproteinase (MT1-MMP), plus the secretion of MMP-7, MMP-9 and the urokinase receptor (uPAR). Chlamydial heat shock protein 60 was identified to be partially responsible for EMMPRIN and MMP-9 induction, while C. trachomatis-infection had no stimulatory effect, indicating a C. pneumoniae-specific activation pathway. Suppression of EMMPRIN by gene silencing almost completely hindered the induction of MT1-MMP and MMP-9 by C. pneumoniae, suggesting a predominant regulatory role for EMMPRIN. Moreover, C. pneumoniae-infected monocytes exhibited increased MMP- and plasmin-dependent migration through "matrigel". Additionally, incubation of SMCs with supernatants of C. pneumoniae-infected monocytes induced MMP-2 activation, which was inhibited by IL1-Receptor antagonist or anti-IL-6-mAb, indicating paracrine intercellular activation pathways. In conclusion, C.pneumoniae induce MMP activity directly in monocytes through an EMMPRIN-dependent pathway and indirectly in SMCs via monocyte-derived cytokines.
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PMID:EMMPRIN (CD 147) is a central activator of extracellular matrix degradation by Chlamydia pneumoniae-infected monocytes. Implications for plaque rupture. 1654 74

Accumulating evidence supports an autoimmune mechanism as one of the prime pathogenic processes involved in the development of atherosclerosis. So far, three proteins, including heat shock proteins (HSPs), oxidized low-density lipoprotein (oxLDL), and beta2 glycoprotein1 (beta2GP1) have been recognized as autoantigens. It has been demonstrated that risk factors for atherosclerosis, such as hypercholesterolemia, hypertension, infections, and oxidative stress, evoke increased expression of HSPs in cells of atherosclerotic lesions. Autoantibody levels against HSPs are significantly increased in patients with atherosclerosis and T lymphocytes specifically responding to these autoantigens have been demonstrated within atherosclerotic plaques. Subcutaneous immunization of animals with HSP65 induced atheroma formation in the arterial wall. Furthermore, circulating immunoglobulin (Ig) G and IgM oxidized low-density lipoprotein (oxLDL) antibodies are present in the plasma of animals and humans and form immune complexes with oxLDL in atherosclerotic lesions. These antibodies closely correlate with the progression and regression of atherosclerosis in murine models. Interestingly, recent reports demonstrated that pneumococcal vaccination to LDL receptor-deficient mice results in elevation of anti-oxLDL IgM Ab EO6, which is inversely correlated with the development of atherosclerosis. Finally, it has been observed that autoantigen beta2GP1 localizes in the atheroma and that autoantibodies to beta2GP1 are correlated with the incidence of atherosclerosis in patients. Hence, these autoimmune reactions to HSPs, oxLDL and beta2GP1 can contribute to the initiation and progression of atherosclerosis.
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PMID:Autoimmune mechanisms of atherosclerosis. 1659 21

It is only some forty years since the discovery of the heat shock or cell stress response and just over twenty years since the heat shock/cell stress response was linked to protein misfolding. The plethora of intracellular proteins which promote correct protein folding in the cell, variously termed molecular chaperones, heat shock proteins, or cell stress proteins, have only been identified in the last fifteen years. During this period it has also been discovered that: (i) molecular chaperones are potent immunogens with immunomodulatory activity and (ii) they can be secreted by cells and exhibit intercellular signaling actions. These various functions of molecular chaperones are increasingly being linked to the pathology of the cardiovascular system. Molecular chaperones within cells can exhibit cardioprotection if their levels are artificially elevated, suggesting that these proteins may have therapeutic activity. In contrast, there is evidence that atherogenesis may be linked to immunity to one specific molecular chaperone, Hsp60. This may offer the possibility of treating atherosclerosis by vaccination. However, there is also growing evidence that secreted molecular chaperones have pro- or anti-inflammatory actions that are relevant to cardiovascular pathology. This review brings these various strands of research together to provide an overview of the role of molecular chaperones in cardiovascular disease.
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PMID:Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease. 1714 Dec 5


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