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)

Inflammation is known to be a major component of atherosclerosis, and cigarette smoking is known to induce a systemic inflammatory response. We therefore, investigated possible gene-environment interactions between various inflammation-related gene polymorphisms and cigarette smoking on the risk of myocardial infarction (MI) in the Physician's Health Study (PHS), a cohort of initially healthy middle-aged men. We used a nested case-control design consisting of 522 MI cases and 2,089 controls derived from PHS. Eleven inflammatory polymorphisms were studied using logistic regression analysis: eotaxin (ala23thr), intercellular adhesion molecule 1 (gly241arg), interleukin-4 (582C>T), interleukin-4 receptor (ile75val, gln576arg), interleukin-6 (-174G>C), interleukin-10 (-571C>A), P-selectin (val640leu, thr756pro, ser330asn), and vascular cell adhesion molecule 1 (-1594T>C). Interactions of smoking with all the three modes of inheritance (additive, dominant, recessive) were tested. Statistically significant (P<0.05) interaction terms were found for interleukin-4 receptor (ile75val), with odds ratios of 0.52 (95%CI:0.29-0.95) for Ile-Val and 0.34 (95%CI:0.14-0.83) for Val-Val, compared to the wildtype Ile-Ile; for interleukin-6 (-174G>C) with odds ratios of 2.16 (1.14-4.09) for GC and 0.81 (0.31-2.12) for CC, compared to the wildtype GG; and for P-selectin (ser330asn) with odds ratios of 0.48 (0.24-0.95) for Ser-Asn and 1.08 (0.29-3.93) for Asn-Asn, compared to the wildtype Ser-Ser, with these effects occurring only among the smokers. These data raise the possibility of interaction between the smoking status and certain inflammatory polymorphisms on the risk of MI in men. However, these results should be interpreted with caution due to the potential for false positive results that can arise from analyses with multiple comparisons.
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PMID:Interaction between inflammation-related gene polymorphisms and cigarette smoking on the risk of myocardial infarction in the Physician's Health Study. 1618 5

Understanding of the mechanisms underlying atherosclerotic disorders has evolved beyond the view of a progressive collection of lipids and cellular debris in the vascular wall. Current evidence has implicated inflammatory pathways as an important pathogenic mechanism in atherogenesis and plaque destabilization. Although not necessarily the primary event, inflammation and cytokine activation during plaque formation and destabilization may represent a common final pathway to various stimuli. Thus, it seems that not only 'new' risk factors, such as infections with various microorganisms, but also classic risk factors for cardiovascular disease, such as hyperlipidemia, hypertension and diabetes, may promote their atherogenic effects through inflammatory responses. Indeed, recent reports have suggested that traditional cardiovascular medications may attenuate atherogenesis and enhance plaque stability, at least partly through anti-inflammatory mechanisms. However, uncovering the inflammatory pathways in atherosclerosis has raised the possibility that newer treatment modalities should be more directly targeted against inflammatory mediators. Recently, a series of experimental studies have reported reduction of atherosclerosis by immunomodulatory therapy, such as chemokine blockade, interleukin-10 and immunization/vaccination against oxidized low-density lipoprotein and heat-shock protein. It is conceivable that some of these approaches will be tested clinically and, if successful, they could provide novel treatment strategies in coronary artery disease in humans.
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PMID:Inflammation in coronary artery disease: potential role for immunomodulatory therapy. 1629 1

Atherosclerosis is an inflammatory disease of the arteries. Interleukin-10 (IL-10) is known to be an anti-inflammatory cytokine which might be useful for counteracting the development of atherosclerosis. As long-term systemic cytokine delivery is prohibitively expensive, gene therapy might be a suitable approach. To test this idea, low-density lipoprotein receptor (LDLR) knockout mice were injected with recombinant adeno-associated virus type 2 (AAV)/interleukin-10 virus or AAV/granulocyte macrophage-colony stimulating factor (GM-CSF) virus and then put on a high-cholesterol diet. Upon harvesting the animals at 18 weeks, elevated blood lipids could be documented and AAV/IL-10 and AAV/GM-CSF DNA and mRNA could be found in various mouse organs. The mice receiving the AAV/IL-10 virus had significantly lower levels of atherogenesis (Sudan IV-staining and histology) than the untreated or the AAV/GM-CSF-treated animals, dropping from 53% to 17% (p < 0.05). The aortas of the AAV/IL-10-treated animals displayed higher IL-10 expression and lower CD68 and nitrotyrosine expression. These data are similar to those of Yoshioka et al. [Yoshioka, T, Okada, T, Maeda, Y, et al. Adeno-associatedvirus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice. Gene Ther 2004;11:1772-9] in which AAV/IL-10 was delivered into the tibial muscle of ApoE-deficient mice, instead of tail vein injection used here. These data indicate that systemic AAV/IL-10 gene delivery, with resulting inhibition of inflammation and oxidative stress, was able to limit atherogenesis, and suggest that this approach is worthy of further study.
Atherosclerosis 2006 Sep
PMID:Inhibition of atherogenesis in LDLR knockout mice by systemic delivery of adeno-associated virus type 2-hIL-10. 1630 Jul 68

Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.
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PMID:Cytokines in atherosclerosis: pathogenic and regulatory pathways. 1660 Dec 68

Highly efficient systems remove the toxic and proinflammatory haemoglobin from the circulation and local sites of tissue damage. Macrophages are major haemoglobin-clearing cells; CD163 was recently recognized as the specific haemoglobin scavenger receptor (HbSR). It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection and inflammation. Haemoglobin functions as a double-edged sword. In moderate quantities and bound to haptoglobin, it forms a ligand for haemoglobin scavenger receptor CD163/HbSR, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. CD163/HbSR plays a crucial role in the control of inflammatory processes, probably in part through its effects on both ferritin induction and subsequent induction of antiinflammatory pathways through interleukin-10 and haem oxygenase. Besides the observation that the haemoglobin scavenger receptor provides a promising target for new treatment possibilities, it offers a novel view on the aetiology of diverse physiological as well as pathophysiological processes. In addition, monocyte CD163/HbSR and soluble CD163/HbSR are potential diagnostic tools in a variety of disease states, such as inflammation, atherosclerosis, transplant rejection, and carcinoma.
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PMID:Haemoglobin scavenger receptor: function in relation to disease. 1677 Apr 44

Chronic low-grade systemic inflammation is a feature of chronic diseases such as cardiovascular disease and type 2 diabetes. Regular exercise offers protection against all-cause mortality, primarily by protection against atherosclerosis and insulin resistance and there is evidence that physical training is effective as a treatment in patients with chronic heart diseases and type 2 diabetes. Regular exercise induces anti-inflammatory actions. During exercise, IL-6 (interleukin-6) is produced by muscle fibres. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra (interleukin-1 receptor antagonist) and IL-10 (interleukin-10) and inhibits the production of the pro-inflammatory cytokine TNF-alpha (tumour necrosis factor-alpha). In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. It is suggested that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine, that is produced and released by contracting skeletal muscle fibres, exerting its effects in other organs of the body. Myokines may be involved in mediating the beneficial health effects against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.
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PMID:The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. 1714 83

The zinc finger transcription factor Egr-l plays an important role in cardiovascular biology. While binding complementary motifs on DNA in the target genes, Egr-1 either increases or decreases proteosynthesis of many proinflammatory and antiinflammatory mediators. In physiologic circumstances, these mediators support healing and regeneration of damaged tissue, mainly by conducting angioneogenesis. In pathologic circumstances these same mediators take an active part in promoting tissue injury. The participation of the transcription factor Egr-1 in the pathogenesis of atherosclerosis can be traced from the initial phases with the generation of foam cells as far as the onset of acute cardiovascular or cerebrovascular ischemic events. At the same time, transcription factor Egr-1 presents a would-be linker at the level of which converge many seemingly heterogenous atherogenic risk factors such as hyperlipidemic disorders, untoward rheologic changes of blood flow often encountered in arterial hypertension or various infectious agents, with Chlamydia pneumoniae belonging to the most deeply investigated ones. Protective effects of the known anti-atherogenic factors, such as the endogenous antiinflammatory cytokine interleukin-10 or the "pleiotropic" effects of statins can be, at least in part, explained by their inhibitory influence on the activities of the transcription factor Egr-1.
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PMID:[Transcription factor Egr-1 in cardiovascular biology]. 1755 70

The offspring of type 2 diabetic patients are at elevated risk for type 2 diabetes and cardiovascular disease. The aim of our study was to characterize the role of various biomarkers of endothelial activation in a cohort of offspring of type 2 diabetic subjects and to assess the association of adhesion molecules with inflammatory markers and metabolic parameters. Cytokine and adhesion molecule levels were measured in 19 healthy subjects and in 129 offspring of patients with type 2 diabetes (109 with normal glucose tolerance and 20 with impaired glucose tolerance). Insulin sensitivity was determined with the hyperinsulinemic-euglycemic clamp, insulin secretion with the intravenous glucose tolerance test, and abdominal fat distribution with computed tomography. The levels of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-Selectin and vascular adhesion protein-1 were not increased in offspring of type 2 diabetic subjects, but they correlated with inflammatory markers (C-reactive protein, tumor necrosis-alpha, interleukin-6, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin-8, interleukin-10 and interleukin-18). In conclusion, the levels of adhesion molecules were not elevated in the prediabetic state. Inflammatory markers and adhesion molecules were correlated suggesting that low-grade inflammation may precede the elevation of levels of adhesion molecules.
Atherosclerosis 2008 Mar
PMID:Markers of endothelial dysfunction and low-grade inflammation are associated in the offspring of type 2 diabetic subjects. 1756 May 80

Inflammatory mechanisms are involved in initiation and progression of atherosclerotic lesions. Previous studies demonstrated antiinflammatory and consecutive antiatherosclerotic effects of the adenosine analogue 3-Deazaadenosine (c(3) Ado) on early lesion development. The present study evaluated the effect of long-term administration of c(3) Ado in a mouse model of advanced atherosclerosis. Apolipoprotein E-deficient mice (age, 35 weeks; n = 31) with already established advanced atherosclerotic lesions were fed either a diet supplemented with c Ado or a regular chow diet for 21 weeks. Treatment resulted in a significant reduction of serum homocysteine levels. Lesion size and lesion morphology, such as frequency of intraplaque hemorrhage, size of necrotic cores, thickness of fibrous caps, and macrophage content within the plaque, were not different between the groups. Lesion calcification, expression of alpha-actin, and intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, were inhibited by treatment with c(3) Ado. We could not detect any effect on serum concentrations of interleukin-10 (IL-10) and interleukin-1beta (IL-1beta) or on soluble adhesion molecules intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Electromobility shift assays of protein extracts isolated from aortas did not demonstrate different binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) after treatment with c Ado. Long-term treatment with the adenosine analogue 3-Deazaadenosine did not show significant effects on progression and stability of advanced atherosclerotic lesions in older apolipoprotein E-deficient mice. A potential antiatherosclerotic effect of c(3)Ado (eg, mediated through inhibition of adhesion molecules) might therefore be limited to prevention of early lesion formation and does not seem to play a relevant role in modifying advanced atherosclerotic disease.
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PMID:Long-term administration of 3-deazaadenosine does not alter progression of advanced atherosclerotic lesions in apolipoprotein E-deficient mice. 1770 38

Cerebrovascular disease is a significant cause of morbidity and mortality in the world. Inflammatory processes induce several pathological responses such as atherosclerosis, which have fundamental roles in stroke in the etiology of ischemic cerebrovascular disease and the pathophysiology of cerebral ischemia. Viral interleukin-10 (vIL-10), a potential anti-inflammatory cytokine, has been studied extensively. However, the efficacy of vIL-10 on cerebrovascular dysfunction is not well known. Our goal in this study was to explore the effect of gene transfer of vIL-10 mediated by adenovirus (Ad/vIL-10) on cerebrovascular function using a model of vasocontraction of isolated basilar artery from mongrel dogs induced by lysophosphatidylcholine (lysoPC), a proinflammatory and atherogenic serum lysophospholipid. To clarify the relation between contraction of basilar aorta and cell adhesion and adhesion molecules, our further study explored effects of Ad/vIL-10 on monocyte-cerebrovascular endothelial cells adhesion and expression of cell adhesion molecule by cultured cerebromicrovascular endothelial cells, bEnd.3, after incubation by lysoPC. Our results showed that Ad/vIL-10 significantly decreased contractive response of basilar aorta produced by lysoPC and augmented vasorelaxation to acetylcholine. Further studies showed the Ad/vIL-10 significantly depressed adherence of monocytes to cerebrovascular endothelial cells and inhibited up-regulation of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) which are bio-markers in inflammatory progress. These data demonstrated the protective effects of Ad/vIL-10 on cerebrovascular dysfunction induced by inflammation, and proved that inhibition of expression of cell adhesion molecules should be one of ways of vIL-10 to protect vascular function during inflammation.
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PMID:Adenoviral gene transfer of viral interleukin-10 protects cerebrovascular impairment induced by lysophosphatidylcholine. 1815 52


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