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)

The interest in Lp(a) lipoprotein [Lp(a)] has increased dramatically during the last few years due to the documented strong association between high Lp(a) levels and early atherosclerosis and its sequelae and the probable additional thrombogenic effect of inherited high Lp(a) levels. However, some paradoxes still remain to be solved in Lp(a) research. This pilot study was performed to test whether some criteria could be found for an association between Lp(a) levels, HLA genotype, and early coronary heart disease. If so, it could help to explain why some individuals with high Lp(a) levels get atherosclerosis while others with comparable lipid levels do not. It would also indicate that immunological processes could be involved in Lp(a) associated atherosclerosis. In this case-control study the HLA-DR genotypes 13 or 17 were significantly more frequently encountered in 30 male patients with early coronary heart disease than in 30 sex and age matched healthy controls (P = 0.012). These HLA-DR specificities were especially frequent in male patients with high Lp(a) levels. The same HLA-DR genotype pattern was not seen in 30 female patients, although there was a trend towards more frequent 13a genotype.
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PMID:Lp(a) lipoprotein and HLA-DR genotype in early coronary artery disease. 849 73

Oxidized low density lipoproteins (oxLDL) stimulated human blood T cells to a specific cytotoxic response with autologous PHA activated blood mononuclear cells which had been pre-incubated with oxLDL. The cytotoxic reaction was exerted by CD8+ enriched cells but not by CD4+ enriched cells. Allogeneic target cells from HLA mismatched donors were not damaged and the reaction was consistently inhibited by monoclonal antibody against HLA class I. Antigen-specific cytotoxic T cells might contribute to lysis of cells in the atherosclerotic plaque that have taken up oxLDL and thus participate in the inflammatory process associated with atherosclerosis.
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PMID:Induction of human cytotoxic T lymphocytes by oxidized low density lipoproteins. 866 16

The exceptionally strong independent association found between Lp(a) lipoprotein [Lp(a)] levels and atherosclerotic disorders indicate that Lp(a) is a factor of considerable importance in the pathogenesis of atherosclerosis. The association between Lp(a) and diabetes, rheumatoid arthritis and renal diseases suggest that Lp(a) may be involved in immunological mechanisms. Lp(a) has a great tendency to aggregate and bind to glucosaminoglycans, fibrin and fibronectin and is preferentially retained in the extracellular matrix during development of atherosclerosis and is in vitro phagocytosed by macrophages, probably as small aggregates. It was previously found that the Lp(a) level is significantly related to the HLA class II genotype in male patients with early coronary artery disease. In this paper additional results of interleukin determinantions in relation to HLA type and Lp(a) levels are presented and discussed. It is suggested that an autoimmune process, perhaps triggered by a concomitant intracellular infection may occur, especially in patients with inherited high Lp(a) levels in combination with certain inherited HLA class II genotypes.
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PMID:Indications of an autoimmune component in LP(a) associated disorders. 909 40

The major limitation to long term survival of organ allografts is chronic rejection, which is manifested as atherosclerosis of the vessels of the transplanted organ. There is a significant association between transplant atherosclerosis and the development of Abs to the disparate HLA Ags present on the graft vasculature. We have investigated the effect of anti-HLA Abs on endothelial cells (EC) and smooth muscle cells cultured in vitro. Ab ligation of class I molecules on ECs results in increased high affinity fibroblast growth factor receptor mRNA expression, and enhanced basic fibroblast growth factor ligand binding. Ab binding to class I molecules on EC and smooth muscle cells is also accompanied by augmented cell proliferation. These results suggest that the intimal thickening observed in transplant atherosclerosis is the result of the proliferative effects of anti-HLA Abs.
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PMID:Induction of high affinity fibroblast growth factor receptor expression and proliferation in human endothelial cells by anti-HLA antibodies: a possible mechanism for transplant atherosclerosis. 954 14

The development of transplant atherosclerosis, a manifestation of chronic rejection, is the major obstacle to long-term survival of cardiac and renal allografts. The incidence of transplant atherosclerosis is increased in transplant recipients producing antidonor HLA antibodies following transplantation, suggesting that anti-HLA antibodies play a role in the pathogenesis of the disease. We have postulated that anti-HLA antibodies mediate the development of transplant atherosclerosis by binding to class I molecules on the endothelium and smooth muscle of the graft and transducing signals which stimulate cell proliferation. In this report we demonstrate that anti-HLA class I antibodies transduce signals in smooth muscle cells stimulating increased tyrosine phosphorylation of intracellular proteins and up-regulation of fibroblast growth factor (FGF) receptors. Antibody binding to class I molecules on smooth muscle cells is also accompanied by increased responsiveness to basic FGF and augmented cell proliferation. These findings may explain the increased occurrence of transplant atherosclerosis in recipients producing anti-donor HLA antibodies.
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PMID:Ligation of HLA class I molecules on smooth muscle cells with anti-HLA antibodies induces tyrosine phosphorylation, fibroblast growth factor receptor expression and cell proliferation. 978 31

Chronic rejection is the major limiting factor to long term survival of solid organ allografts. The hallmark of chronic rejection is transplant atherosclerosis, which is characterized by the intimal proliferation of smooth muscle cells, endothelial cells, and fibroblasts, leading to vessel obstruction, fibrosis, and eventual graft loss. The mechanism of chronic rejection is poorly understood, but it is suspected that the associated vascular changes are a result of anti-HLA Ab-mediated injury to the endothelium and smooth muscle of the graft. In this study we have investigated whether anti-HLA Abs, developed by transplant recipients following transplantation, are capable of transducing signals via HLA class I molecules, which stimulate cell proliferation. In this report we show that ligation of class I molecules with Abs to distinct HLA-A locus and HLA-B locus molecules results in increased tyrosine phosphorylation of intracellular proteins and induction of fibroblast growth factor receptor expression on endothelial and smooth muscle cells. Treatment of cells with IFN-gamma and TNF-alpha up-regulated MHC class I expression and potentiated anti-HLA Ab-induced fibroblast growth factor receptor expression. Engagement of class I molecules also stimulated enhanced proliferative responses to basic fibroblast growth factor, which augmented endothelial cell proliferation. These findings support a role for anti-HLA Abs and cytokines in the transduction of proliferative signals, which stimulate the development of myointimal hyperplasia associated with chronic rejection of human allografts.
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PMID:Alloantibody-mediated class I signal transduction in endothelial cells and smooth muscle cells: enhancement by IFN-gamma and TNF-alpha. 1039 99

Takayasu arteritis is a chronic vasculitis, mainly involving the aorta and its main branches as well as the coronary and pulmonary arteries, causing stenosis and/or obstruction due to thrombus formation or dilatation due to aneurysmal formation and/or rupture of the involved arteries. These characteristic anomalies resulted from ischemia of retinal arteries due to the obstruction of cervical vessels. In Western countries this disease is also known as "pulseless disease," because the pulse is frequently absent due to the obstruction of subclavian or branchial arteries. The pathogenesis of this morbid condition is still unknown. Epidemiologically, it is found mostly in female patients and is more prevalent in Asian and Latin American countries. Affected areas consist of a mixture of both active, productive inflammatory lesions, and old fibrous lesions. Autoimmune processes stimulated by viral infection and other unknown causative factors may play an important role under these pathophysiological conditions because HLA analysis revealed a statistically significant high frequency of haplotype A24-B52-DR2 in these patients in Japan. Documentation of atherosclerotic complications in young female patients with Takayasu arteritis who are generally free from traditional atherosclerosis risk factors may be clinical evidence that inflammation is indeed an important risk factor in atherogenesis.
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PMID:Inflammation and atherosclerosis. Atherosclerotic lesions in Takayasu arteritis. 1086 26

Takayasu arteritis, Buerger's diseases, temporal arteritis, vascular Behcet disease and inflammatory abdominal aortic aneurysm are classified in Japan as intractable vasculitides involving mainly large vessels, because their etiologies are not yet elucidated and, therefore, treatments for them were not yet established. Recent experimental and vascular biological studies, however, have focussed on the roles of virus infection in vasa vasorum (vasa vasoritis) and on the subsequent inflammatory vascular changes through HLA and/or other autoimmune mechanisms. Several studies including ours have demonstrated that these vascular inflammatory changes progress from the adventitial side to the intimal side of the vessel, finally complicating atherosclerotic changes in the intima. These vascular inflammatory changes are also recognized during progression of atherosclerosis and these observations strongly suggest that inflammation is a serious risk factor of atherosclerosis.
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PMID:Vasa vasoritis, vasculitis and atherosclerosis. 1098 Mar 30

Autoimmune-target cells in autoimmune disease (AID) are usually construed as constitutionally normal healthy cells. A related assumption is that other cells in the body of AID patients, except for certain immunocytes, are healthy cells. An implication of that view is that any systemic pathology in organ-specific AID is related to metabolic derangements secondary to tissue destruction. However, much data on target and other cells in AID suggest widespread primary cellular defects. In insulin-dependent diabetes mellitus (IDDM), for example, many "complications" such as atherosclerosis, premature arterial stiffening, senescence of fibroblasts in vitro, and exuberant growth of smooth muscle and mesangial cells in vivo are not strictly attributable to glucose elevation. Also unexplained is the similar appearance of IDDM beta-cells and cells from insulinoma and why the prodromal phase of IDDM has many insulinoma-like features. While AID target cells have often been likened to neoplastic cells, investigators have rarely explored the possibility that autoimmunity in AID is fundamentally antineoplastic. This is likely because the dominant ideas in oncology and immunology-somatic mutation and clonal deletion, respectively-have prevented explanations for how normal immunity could detect transforming cells not expressing non-self antigens. New and less conventional theories of cancer and immunity have facilitated such an explanation. I use Rubin's "epigenetic" aging model of carcinogenesis and Matzinger's "danger" model of immunity to integrate the immunological and oncological sides of AID. In particular, I postulate that individuals suffering from AID have inherited many foci of prematurely aging cells. Those inherently damaged cells adapt to in vivo challenges by beginning to transform into cancer cells. However, as long as those stressed cells have not fully transformed, they will continue to signal "danger" to the innate immune system. The clinical outcome of that struggle between incipient neoplasia and immunity will vary depending upon the degree of tumor-proneness and resistance of the individual. Borrowing from cancer geneticist Henry Lynch, I postulate that tumor-resistance is inherited as a quantitative polygenic trait in direct proportion to tumor-proneness. I further contend that tumor-proneness and immunity are linked polygenic traits such that the greater one's tumor-proneness, the more powerful his/her antitumor immunity. I point to the shared DNA repair deficiency of certain cancer-prone syndromes and HLA-linked AID, their occasional co-occurrence, and their demonstrably exceptional immunity against solid tumors. I propose that HLA-linked AID constitute "chronic hypersensitivity syndromes" due to immunity's largely hidden battle to suppress multiple incipient neoplastic microfoci. Much of the physiopathology of AID is explicable as a sustained systemic response to threatened neoplastic transformation.
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PMID:Hypothesis. Bystanders or bad seeds? Many autoimmune-target cells may be transforming to cancer and signalling "danger" to the immune system. 1126 91

The long-term success of renal transplantation is limited because of chronic rejection (CR), which shows histologic parallels to atherosclerosis. Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis, but its role in CR has not been investigated. Plasma levels of Lp(a) are determined mainly by the inherited isoform (phenotype) of apolipoprotein(a) [apo(a)] and show an inverse correlation with the molecular weight of apo(a). Apo(a) isoforms were identified in frozen sera of 327 patients who received a renal transplant during 1982 to 1992. Long-term graft survival in recipients with high molecular weight (HMW) or low molecular weight (LMW) apo(a) phenotypes were compared retrospectively. Mean (95% confidence interval) transplant survival was 12.8 yr (range, 11.9 to 13.6 yr) in patients with HMW and 11.9 yr (range, 10.8 to 13.1 yr) in patients with LMW apo(a) phenotypes (P = 0.2065). In patients who were 35 yr or younger at the time of transplantation, mean transplant survival was more than 3 yr longer in recipients with HMW apo(a) phenotypes compared with those with LMW apo(a) phenotypes (13.2 yr [range, 12.1 to 14.4 yr] versus 9.9 yr (range, 8.5 to 11.5 yr); P = 0.0156). In a Cox's proportional hazards regression model, the presence of LMW phenotypes-but not gender, immunosuppression, or HLA mismatches-in young patients was associated with a statistically significant risk of CR (P = 0.0434). These retrospective data indicate that young renal transplant recipients with LMW apo(a) phenotypes have a significantly shorter long-term graft survival, regardless of the number of HLA mismatches, gender, or immunosuppressive treatment.
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PMID:Impact of apolipoprotein(a) phenotypes on long-term renal transplant survival. 1131 65


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