Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The studies discussed have established that inflammatory or immune cytokines, such as IL-1, TNF, and LT, as well as bacterial endotoxin, can act directly on vascular endothelial cells to modulate two important functional properties. The first of these, the inducible expression of E-LAMs, provides a mechanism for the local regulation of leukocyte-vessel wall interactions. This endothelial-dependent mechanism may be relevant to a broad spectrum of pathologic processes, including inflammation, delayed hypersensitivity reactions, and atherogenesis. The second, modulation of endothelial tissue factor PCA and fibrinolytic components, has important implications for the local balance of prothrombotic and antithrombotic influences at the blood-vessel wall interface. Thus, under the influence of inflammatory stimuli, vascular endothelial cells may actively contribute to the development and maintenance of intravascular or perivascular fibrin. Although the endothelial effector mechanisms of these functional alterations are distinct, their induction by similar stimuli points to important interrelationships of leukocyte-vessel wall adhesion and thrombosis. Further understanding of the regulation of endothelial expression of E-LAMs and coagulant properties should contribute to our understanding of vascular disease.
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PMID:Inducible endothelial functions in inflammation and coagulation. 312 25

Many clinical and experimental data are in favour of a participation of leukocytes in vascular disease. Diabetes, a risk factor, is associated with a dysfunction of neutrophils. If chemotaxis and phagocytosis are deficient, it is not clearly established whether superoxide generation is conserved in these patients. We have measured this function in 35 noninsulin dependent diabetic patients, compared with a control population. We have assessed, in parallel, a profile of the cytokines involved in vascular phenomenons including TNF alpha, IL-1 beta et IL-6. Our results indicate that the generation of free radicals is normal in diabetics, with a significant elevation of TNF alpha. These results suggest a possible participation of this cytokine in the modulation of granulocyte reactivity.
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PMID:[Respiratory burst of neutrophils and cytokine profile in the non-insulin-dependent diabetic]. 765 Apr 34

Visceral fat accumulation often accompanies various complications, such as insulin resistance, hypertension, dyslipidemia and atherosclerosis. Adipose tissue has been found to secrete various biologically active adipocytokines including free fatty acids. Accumulation of visceral fat increases the portal free fatty acids concentration to cause insulin resistance and dyslipidemia. Tumor necrosis alpha (TNF alpha) deteriorates insulin resistance in obesity. The levels of plasminogen activator inhibitor(PAI)-1 increase and plasma adiponectin concentration decreases in obesity leading to the development of vascular disease. The finding of genes specifically expressed in visceral fat and new adipocytokines should facilitate clarification of the mechanism for the development and complications of visceral fat accumulation.
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PMID:[Molecular mechanism in the development of the complications associated with obesity--the physiological and pathological role of adipocytokines]. 1126 96

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

The insulin resistance syndrome (IRS) with obesity is large-word wide-spread and represents a strong risk factor for vascular disease. Atherothrombotic complications in IRS are partly attributed to a dysregulation of hemostasis inducing a prothrombotic state which includes endothelial activation, hyperactivity of platelets, hypercoagulability and hypofibrinolysis. This latter, due to elevated PAI-1 levels, is a core feature of the IRS. Most of the prothrombotic modifications can be reversed by loosing weight. Low grade inflammation with prolonged cytokines mediated acute phase reaction is actually considered as strongly related to the IRS and is involved in the dysregulation of hemostasis. TNF pathway and TGFb play an important role in the regulation of PAI-1 synthesis in the adipose tissue and the liver with steatosis. Interestingly, modulation of PAI-1 expression in adipose tissue influences adipose tissue growth, increasing once more the spectrum of the non hemostatic functions of coagulation/fibrinolysis parameters.
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PMID:The insulin resistance syndrome: implications for thrombosis and cardiovascular disease. 1367 55

Previously we demonstrated that aging in coronary arteries is associated with proinflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by enhancing endothelial apoptosis. To test this hypothesis we characterized proapoptotic alterations in the phenotype of coronary arteries of aged (26 mo old) and young (3 mo old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was an approximately fivefold increase in the number of apoptotic endothelial cells. In aged coronary arteries there was an increased expression of TNFalpha, TNFbeta, and caspase 9 (microarray, real-time PCR), as well as increased caspase 9 and caspase 3 activity, whereas expression of TNFR1, TNFalpha-converting enzyme (TACE), Bcl-2, Bcl-X(L), Bid, Bax, caspase 8, and caspase 3 were unchanged. In vessel culture (18 h) incubation of aged coronary arteries with a TNF blocking antibody or the NO donor S-nitroso-penicillamine (SNAP) decreased apoptotic cell death. Incubation of young arteries with exogenous TNFalpha increased caspase 9 activity and elicited endothelial apoptosis, which was attenuated by SNAP. Inhibition of NO synthesis in cultured young coronary arteries also induced apoptotic cell death and potentiated the apoptotic effect of TNFalpha. Thus we propose that age-related upregulation of TNFalpha and caspase 9 and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to impaired endothelial function and ischemic heart disease in the elderly.
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PMID:Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging. 1502 Jul 20

Genetic studies in familial lung fibrosis have demonstrated an association with surfactant protein C genes: two mutations have been found resulting in protein misfolding and causing type-II epithelial cell injury. Remarkably, different histological patterns were observed in the affected subjects, suggesting the influence of modifier genes and/or environmental factors. Surfactant protein C gene variations have not, however, been associated with sporadic cases, i.e. idiopathic pulmonary fibrosis (IPF). Susceptibility to IPF probably involves a combination of polymorphisms related to epithelial cell injury and abnormal wound healing. To date, the genetic associations with IPF that have been reported in different cohorts include the genes encoding tumour necrosis factor (TNF; -308 adenine), interleukin-1 receptor antagonist (+2018 thymidine) and association with severity and progression (interleukin-6/TNF receptor II and transforming growth factor-beta1 (TGFB1; +869 cytosine)), but none of these associations have been replicated by others. Unlike in IPF, immunological inflammation seems to be more prominent in the pathogenesis of scleroderma lung fibrosis, being an autoimmune disease with specific autoantibodies, such as antitopoisomerase antibodies, in patients with diffuse lung disease, and anticentromere antibodies, in patients with pulmonary vascular disease. Antitopoisomerase antibody positivity is associated with the carriage of human leukocyte antigen DRB1*11 and DPB1*1301 alleles, suggesting the recognition of a specific amino-acid motif. Extended haplotype analysis also supports the conclusion that TNF may be the primary association with anticentromere positivity. Intriguingly, associations with TGFB1 and genes involved in extracellular matrix homeostasis have been reported in this disease. In conclusion, significant steps forward have been taken in the understanding of the genetic contribution to fibrosing lung diseases, but major challenges lay ahead. It is the present authors' opinion that only a combined approach studying large numbers of familial and sporadic cases, all clinically well phenotyped, using multiple distinct cohorts, and genotyped according to relevant gene ontologies will be successful. It will be necessary to be particularly vigilant with regard to phenotype; the absence of very strong reproducible associations may be because of the rigidity of phenotype definition, coupled with the possibility that idiopathic pulmonary fibrosis may still be a heterogeneous group of diseases, despite the more rigid definition set out by the European Respiratory Society/American Thoracic Society statement.
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PMID:Genetics of fibrosing lung diseases. 1586 52

Heme oxygenase 1 (HO-1) plays an important role in vascular disease, transplantation, and inflammation. In animal models of acute and chronic inflammation, induction of HO-1 has anti-inflammatory and cytoprotective properties. Since inflammation is an important trigger of osteoclastogenesis, we hypothesized that HO-1 might influence osteoclastogenesis. We investigated the effects of induction of HO-1 on osteoclast formation in vitro and in vivo. Furthermore, we addressed the role of HO-1 in inflammatory bone loss in humans. When HO-1 was induced by hemin in vitro, a significant dose-dependent inhibition of osteoclastogenesis was observed. Up-regulation of HO-1 was mediated by activation of MAPK and primarily prevented differentiation of osteoclast precursors to osteoclasts, whereas it did not affect mature osteoclasts. Anti-osteoclastogenic properties of hemin were based on a down-regulation of c-fms, RANK, TRAF-6, and c-fos. In addition, induction of HO-1 inhibited TNF-triggered osteoclast differentiation in vitro as well as LPS-driven inflammatory bone loss in vivo. Furthermore, HO-1 induction suppressed osteoclastogenesis and bone destruction in a TNF-mediated arthritis. In line, assessment of synovial tissue from rheumatoid arthritis patients revealed that osteoclasts are usually HO-1 negative. Moreover, serum levels of bilirubin, a metabolite of HO-1, were elevated in rheumatoid arthritis patients without bone damage, suggesting HO-1 affects bone loss in humans. In summary, these data indicate that HO-1 negatively regulates osteoclastogenesis, leading to a positive net balance of bone.
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PMID:Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption. 1623 31

Dendritic cells are the major antigen-presenting and antigen-priming cells of the immune system. We review the antigen-presenting and proinflammatory roles played by dendritic cells in the initiation of rheumatoid arthritis (RA) and atherosclerosis, which complicates RA. Various signals that promote the activation of NF-kappaB and the secretion of TNF and IL-1 drive the maturation of dendritic cells to prime self-specific responses, and drive the perpetuation of synovial inflammation. These signals may include genetic factors, infection, cigarette smoking, immunostimulatory DNA and oxidized low-density lipoprotein, with major involvement of autoantibodies. We propose that the pathogenesis of RA and atherosclerosis is intimately linked, with the vascular disease of RA driven by similar and simultaneous triggers to NF-kappaB.
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PMID:Cells of the synovium in rheumatoid arthritis. Dendritic cells. 1785 Jun 83

We investigated the role of CD40 and CD40L in neointima formation and identified the downstream CD40-signaling intermediates (tumor necrosis factor [TNF]-receptor associated factors [TRAF]) involved. Neointima formation was induced in wild-type, CD40(-/-), CD40L(-/-), and in CD40(-/-) mice that contained a CD40 transgene with or without mutations at the CD40-TRAF2,3&5, TRAF6, or TRAF2,3,5&6 binding sites. Compared with wild-type mice, CD40(-/-) mice showed a significant decrease in neointima formation with increased collagen deposition and decreased inflammatory cell infiltration. Neointima formation was also impaired in wild-type mice reconstituted with CD40(-/-) bone marrow. In vitro, the capacity of CD40(-/-) leukocytes to adhere to the endothelium was reduced. Ligated carotid arteries of CD40(-/-) mice showed a smaller total vessel volume and an impaired remodeling capacity, reflected by decreased gelatinolytic/collagenolytic activity. Comparable results were found in mice with defects in CD40-TRAF6 and CD40-TRAF 2/3/5&6 binding, but not in mice with defects in CD40-TRAF2/3&5 binding. Neointima formation and vascular remodeling in CD40-receptor-deficient mice is impaired, due to a decreased inflammatory cell infiltration and matrix-degrading protease activity, with CD40-TRAF6 signaling as the key regulator. This identifies the CD40-TRAF6 axis as a potential therapeutic target in vascular disease.
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PMID:The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling. 1844 Dec 39


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