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)

Apoprotein(a), (apo[a]), the specific antigen of lipoprotein(a) (Lp[a]), consists of structural domains (a serine protease unit, kringles 4 and 5) with marked homology to those of the corresponding domains in plasminogen. In this study, we have investigated the impact of this unique structural mimicry on the binding and activation of plasminogen by fibrin-bound tissue-type plasminogen activator at the plasma-fibrin interface. We found that the total amount of plasmin generated on the surface of fibrin was decreased in the presence of high concentrations of Lp(a): 197 +/- 65 fmol in plasmas with greater than 60 mg/dl Lp(a) versus 287 +/- 112 fmol in control plasmas. A similar effect was also apparent in the corresponding euglobulin fractions (554 +/- 169 fmol versus 754 +/- 310 fmol), the latter lacking the plasminogen-binding proteins alpha 2-antiplasmin and histidine-rich glycoprotein, but containing Lp(a). The difference between plasma samples was significant (p less than 0.05) as calculated from the percent decrease in plasmin generated from plasmas with high levels of Lp(a) relative to that generated in the paired controls with low Lp(a) levels. The involvement of Lp(a) was verified in a reconstituted system consisting of normal human plasma supplemented with 100 mg/dl of either purified Lp(a) or low density lipoprotein. Lp(a) produced a decrease of 30% in the generation of plasmin (180 fmol versus 255 fmol in plasma, and 485 fmol versus 705 fmol in the euglobulin fraction). Moreover, using a radiolabeled sheep antibody against human apo(a), we were able to demonstrate the binding of 40 fmol Lp(a) to fibrin during ongoing plasminogen activation. These results indicate that Lp(a) impairs the binding of plasminogen to fibrin and thereby decreases the generation of plasmin by occupying C-terminal lysine residues unveiled on the fibrin surface by plasmin degradation as recently reported (Circulation 1990;82[suppl III]:III-92). In consequence, impairment of fibrinolysis and accumulation of Lp(a) at sites of vascular injury may occur, factors that may be important in the development of atherosclerosis and associated thrombosis.
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PMID:Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator. In vitro studies in a plasma milieu. 182 91

Lipoprotein(a) (Lp(a)) has been strongly linked with atherosclerosis and is an independent risk factor for myocardial infarction. Distinguishing Lp(a) from other low-density lipoprotein particles is its content of a unique apoprotein, apo(a). The recently described sequence of apo(a) indicates a remarkable homology with plasminogen, the zymogen of the primary thrombolytic enzyme, plasmin. Lp(a) may contain 37 or more disulphide-looped kringle structures, which are 75-85% identical to the fourth kringle of plasminogen. Plasminogen receptors are widely distributed on blood cells and are present at extremely high density on endothelial cells. These receptors promote thrombolysis by accelerating plasminogen activation and protecting plasmin from inhibition. If, by molecular mimicry, Lp(a) competes with plasminogen for receptors, then thrombolysis would be inhibited and thrombosis promoted. Here we provide support for such a mechanism being responsible for the thrombotic risks associated with elevated Lp(a) by demonstrating that Lp(a) inhibits plasminogen binding to cells.
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PMID:A potential basis for the thrombotic risks associated with lipoprotein(a). 254 96

Werner syndrome (WS) is an autosomal recessive disease manifested by the premature onset of age-related phenotypes, including diseases such as atherosclerosis and cancer. This mimicry of normal aging with the possible exception of central nervous system manifestations has made it a focus of recent molecular studies on the pathophysiology of aging. In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions. The WS gene product (WRN) is a DNA helicase belonging to the RecQ family, but is unique within this family in that it also contains an exonuclease activity. In addition to unwinding double-stranded DNA, WRN helicase is able to resolve aberrant DNA structures such as G4 tetraplexes, triplexes and 4-way junctions. Concordant with this structure-specificity, WRN exonuclease preferentially hydrolyzes alternative DNA that contains bubbles, extra-helical loops, 3-way junctions or 4-way junctions. WRN has been shown to bind to and/or functionally interact with other proteins, including replication protein A (RPA), proliferating cell nuclear antigen (PCNA), DNA topoisomerase I, Ku 86/70, DNA polymerase delta and p53. Each of these interacting proteins is involved in DNA transactions including those that resolve alternative DNA structures or repair DNA damage. The biochemical activities of WRN and the functions of WRN associated proteins suggest that in vivo WRN resolves DNA topological or structural aberrations that either occur during DNA metabolic processes such as recombination, replication and repair, or are the outcome of DNA damage.
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PMID:Unwinding the molecular basis of the Werner syndrome. 1134 59

Microbes have been proposed as inciting agents of tissue injury and inflammation, both of which underlie the pathogenesis of atherosclerosis. Viruses, including the herpes simplex virus and cytomegalovirus, as well as bacteria such as Chlamydia pneumoniae, have been implicated in the process. In vitro, these agents promote a proinflammatory and a procoagulant phenotype in vascular cells. Viruses augment cell accumulation through alterations of apoptosis. Infectious agents may play a role in pathogenesis of atherosclerosis by triggering an autoimmune response due to microbial molecular mimicry. It is unlikely that a single agent is the sole cause or modulator of this heterogeneous disease. Contradictory epidemiological studies may be reconciled with a new construct suggesting that multiple pathogens infecting an individual in aggregate may promote an inflammatory and procoagulant environment that underlies the pathogenesis of atherosclerosis.
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PMID:Overview of infections and cardiovascular diseases. 1158 78

Recently, a growing number of epidemiological, histopathological and microbiological studies have shown that chronic Chlamydia pneumoniae (C. pneumoniae) infection accelerates the progression of atherosclerosis of carotid and cerebral arteries and thus could constitute a risk factor for stroke. We present a number of mechanisms postulated in recent papers that link C. pneumoniae infection with the development of atherosclerosis. The one most important seems to be the effect of activation of nuclear factor--kappa B and the phenomenon of antigenic mimicry between human and C. pneumoniae heat shock proteins. We also discuss the problem of immunological reaction against myosin filaments of carotid artery wall smooth muscle cells and the problem of antigenic mimicry between heavy chains of myosin filaments and antigens presented on C. pneumoniae outer membrane.
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PMID:[Effect of Chlamydia pneumoniae infection on carotid atherosclerosis development]. 1205 4

A role of autoimmune process and its link with bacterial infections in initiation or aggravation of atherosclerosis symptoms has been suggested. Antigenic mimicry and cross-reactivity of circulating antibodies have been indicated as some major factors in this process. In this study, the prevalence and titers of IgG and IgA antibodies reacting with glycine extract of H. pylori surface antigens were determined immunoenzymatically (ELISA) in the group of patients with unstable ischaemic heart disease and in patients with aggravated dyspepsia. Our results reveal that elevated titers of IgG anti-H. pylori are more typical for cardiac patients and lower prevalence of IgA anti-H. pylori--for those with aggravated dyspepsia. This supports the hypothesis that intensed humoral response in immunoglobulins class G against some bacterial antigens may play a role in the aggravation of symptoms of coronary atherosclerosis.
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PMID:Patients with unstable angina pectoris present increased humoral response against Helicobacter pylori in comparison with patients with aggravated dyspepsia. 1270 22

During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.
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PMID:Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. 1277 53

Atherosclerosis has long been recognised as having an inflammatory component, and this has a particularly important bearing on to its clinical complications as it may result in plaque instability. Results of recent epidemiological studies have reinforced the potential importance of this aspect of the disease. Positive associations have been reported between exposure to several specific pathogens, and future risk of coronary heart disease (CHD). Whilst it is possible that each individual organism contributes to this susceptibility by a different mechanism, it is more likely that one or more common mechanism(s) exist. One possible hypothesis is that an immune response mounted against antigens on pathogenic organisms cross-react with homologous host proteins in a form of 'molecular mimicry'. A group of protein candidates that may be implicated in this process are the stress-induced proteins collectively known as heat shock proteins (HSP). HSPs are expressed and/or secreted by several pathogens, principally Chlamydia pneumoniae and Helicobacter pylori, but are also elaborated by mammalian vascular cells exposed to the stress associated with reperfusion injury or acute hypertension. The HSPs are also expressed by cells within atherosclerotic plaques. Serum titres of anti-HSP antibodies have been reported to be positively related to future risk of CHD. In addition, purified anti-HSP antibodies recognise and mediate the lysis of stressed human endothelial cells and macrophages in vitro. Furthermore, immunisation with HSP exacerbates atherosclerosis in experimental animal models. Some human vaccines, such as BCG, contain HSPs, hence although vaccination programmes are vital for maintaining 'herd' immunity and the prevention of serious infectious disease, they may leave a legacy of increased susceptibility to atherosclerosis. Development of HSP-free vaccines could satisfy the twin goals of protection from infection and reduced incidence of coronary disease.
Atherosclerosis 2003 Apr
PMID:Molecular mimicry in atherosclerosis: a role for heat shock proteins in immunisation. 1470 75

Recent evidence indicates that infections or a pathogen burden contribute to the development and progression of atherosclerosis. While the mechanism of infection contributing to the pathogenesis is not fully elucidated, I hypothesize that heat shock proteins may be a link between infections and atherosclerosis. Heat shock proteins are a highly conserved family of proteins expressed in most cell types and have been shown to play a general role in protecting cells in response to stress. It has been demonstrated that Chlamydia and human HSP60 coexist in atherosclerotic lesions. Bacterial and human heat shock proteins have been found in soluble form in the general circulation of patients with atherosclerosis. Both heat shock proteins can stimulate cells to express adhesion molecules and proinflammatory cytokines. Certain organisms synthesize heat shock proteins that have close structural homology with human heat shock proteins. Because of the immunologic molecular mimicry between bacterial and human HSP60, it could be an autoantigen involved in eliciting cell-mediated and humoral immune responses that cause vessel injury leading to atherosclerosis. The aim of this review is to provide an update overview on the involvement of heat shock proteins in the pathogenesis of atherosclerosis in response to infections.
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PMID:Infections, heat shock proteins, and atherosclerosis. 1285 20

The large amount of data accumulated in recent years has reinforced the idea that infectious agents may play a significant role in the pathogenesis of atherosclerosis and in the clinical manifestations of vascular disease. Seroepidemiological and experimental data linking Herpesviridae and Chlamydia pneumoniae to atherosclerosis appear to be confirmed by a number of studies, while the available evidence regarding Helicobacter pylori is more conflicting, partly due to the fact that the interest in this agent is more recent. Infectious agents may influence atherogenesis through a number of mechanisms, ranging from cell lysis to the stimulation of adhesion molecule expression and cytokine production by infected cells. The development of atherosclerosis after an acute infection seems unlikely. Rather, it appears that a chronic, persistent form of infection, especially with Chlamydia pneumoniae, may favor those structural and proinflammatory changes in the vascular wall which are necessary for the formation of an atheroma. A persistent chlamydial infection is accompanied by an increased production of microbial heat shock protein 60, which may induce antigenic mimicry and a chronic inflammatory reaction in the vascular wall. Pharmacological trials have yielded conflicting indications regarding the hypothesis that treatment with macrolide antibiotics may limit the progression of vascular disease and the recurrence of cardiovascular events, although in a limited number of cases. However, antimicrobial drugs do not act specifically against a single infectious agent and more specific therapeutic agents would be needed in order to test a causative link between a single infectious agent and vascular disease.
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PMID:Infectious agents and atherosclerosis: current perspectives and unsolved issues. 1518 98


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