Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Transforming growth factor-beta (TGF-beta) is a major antiinflammatory mediator in atherosclerosis. Transgenic ApoE(-/-) mice with a dominant-negative TGFbeta type II receptor (dnTGFbetaRII) on CD4(+) and CD8(+) T cells display aggravated atherosclerosis. The aim of the present study was to elucidate the mechanisms involved in this enhanced inflammatory response. Gene array analyses identified the 5-lipoxygenase-activating protein (FLAP) among the most upregulated genes in both the aorta and adipose tissue of dnTGFbetaRII transgenic ApoE(-/-) mice compared with their ApoE(-/-) littermates, a finding that was confirmed by real-time quantitative RT-PCR. Aortas from the former mice in addition produced increased amounts of the lipoxygenase product leukotriene B(4) after ex vivo stimulation. FLAP protein expression in both the aorta and adipose tissue was detected in macrophages, but not in T cells. Four weeks of treatment with the FLAP inhibitor MK-886 (10 mg/kg in 1% tylose delivered by osmotic pumps) significantly reduced atherosclerotic lesion size and T-cell content. Finally, FLAP mRNA levels were upregulated approximately 8-fold in adipose tissue derived from obese ob/ob mice. In conclusion, the results of the present study suggest a key role for mediators of the 5-lipoxygenase pathway in inflammatory reactions of atherosclerosis and metabolic disease.
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PMID:5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation. 1737 35

Sclerotic calcification of the aortic valve is a common disease in advanced age. Its pathophysiology is unclear. However, pathobiological similarities to atherosclerosis have been shown in several studies. The current study assesses gene profiling of severe calcified stenotic human aortic valves identifying transforming growth factor (TGF)-beta, Eotaxin3, vascular adhesion protein-1 (VAP-1) and monokine induced by interferon-gamma (MIG) as potential atherosclerotic target genes in severe calcified and stenotic aortic valves, and analyzes the effects of statins on their expression as part of an anti-inflammatory treatment strategy. We collected human severe calcified and stenotic aortic valves with (CSAV+) or without (CSAV-) statin pre-treatment prior to valve replacement and investigated gene profiling by using micro-array technique and real-time PCR for the TGF-beta, Eotaxin3, VAP-1 and MIG expression. In comparison to atherosclerotic plaques of carotid arteries, immunohistochemical staining was investigated. Results were contrasted to human normal non-calcified aortic valves as controls (C). As compared to C, TGF-beta, Eotaxin3, MIG or VAP-1 was significantly upregulated in CSAV-. In CSAV+ no significant change in gene expression was found for Eotaxin3 and MIG. In contrast, VAP-1 and TGF-beta were still upregulated. Corresponding gene expression was confirmed on atherosclerotic plaque formations of carotid arteries. Monocyte/Macrophage infiltration (presence of CD68) on aortic valves (CSAV+, CSAV-, or C) confirmed inflammatory nature of the disease. Our data support further evidence for atherosclerotic inflammation as a trigger for sclerosis in end-stage calcified stenotic aortic valves by showing upregulation of gene expression for TGF-beta, VAP-1, MIG and Eotaxin3, which is only partially inhibited by previous statin therapy. Potent benefits of statin treatment on early stages of valve disease are still propagated.
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PMID:VAP-1, Eotaxin3 and MIG as potential atherosclerotic triggers of severe calcified and stenotic human aortic valves: effects of statins. 1749 Jun 41

Hypercholesterolemia is a major causative factor for atherosclerotic cardiovascular disease. The molecular mechanisms by which cholesterol initiates and facilitates the process of atherosclerosis are not well understood. Here, we demonstrate that cholesterol treatment suppresses or attenuates TGF-beta responsiveness in all cell types studied as determined by measuring TGF-beta-induced Smad2 phosphorylation and nuclear translocation, TGF-beta-induced PAI-1 expression, TGF-beta-induced luciferase reporter gene expression and TGF-beta-induced growth inhibition. Cholesterol, alone or complexed in lipoproteins (LDL, VLDL), suppresses TGF-beta responsiveness by increasing lipid raft and/or caveolae accumulation of TGF-beta receptors and facilitating rapid degradation of TGF-beta and thus suppressing TGF-beta-induced signaling. Conversely, cholesterol-lowering agents (fluvastatin and lovastatin) and cholesterol-depleting agents (beta-cyclodextrin and nystatin) enhance TGF-beta responsiveness by increasing non-lipid raft microdomain accumulation of TGF-beta receptors and facilitating TGF-beta-induced signaling. Furthermore, the effects of cholesterol on the cultured cells are also found in the aortic endothelium of ApoE-null mice fed a high-cholesterol diet. These results suggest that high cholesterol contributes to atherogenesis, at least in part, by suppressing TGF-beta responsiveness in vascular cells.
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PMID:Cholesterol suppresses cellular TGF-beta responsiveness: implications in atherogenesis. 1787 31

Atherosclerosis and calcifications in the cardio-vascular system are the most frequent causes of increased morbidity and mortality in patients with end-stage renal disease treated with hemodialyses. The aim of this study was to estimate the atherosclerosis progression and presence of calcifications in the circulatory system in patients treated with hemodialyses using, non-invasive imaging diagnostic techniques and to search for the relationships between these changes and microinflammation and oxidative stress during two years. The study was performed in 73 patients (36 female and 37 male), aged 25 to 75 years (mean -49.5), treated with hemodialyses, 3 times/week for 12 to 275 months (mean -73.8). In each patient before starting hemodialysis levels of: ox-LDL, Lp (a), procalcitonin, IL-1beta, IL-6, CRP, TGFbeta, TNFalpha, PDGF, AOPP and MPO were determined. Presence of artery calcifications was detected by Multi-Row Spiral Computed Tomography (MSCT) and expressed as coronary artery calcification score (CACS). Ultrasonography was used to evaluate CCA-IMT. During the study CACS increased significantly after 12 and 24 months (p < 0.00001) as compare with baseline. After 12 months, CACS increase significantly correlated with procalcitonin level (r = 0.30 p = 0.01) and after 24 months with CRP (r = 0.46; p = 0.0002) and IL-6 (r = 0.36; p = 0.005). Independent factor of coronary artery calcification progression after 24 months of observation was only CRP (beta = 0.569). CCA-IMT increased during the study and this increase was statistically significant (p < 0.00001). CCA-IMT increase correlated with CACS growth after 12 (r = 0.36; p = 0.003) and 24 months (r = 0.39; p = 0.002). After 12 months significant relationship was noted with procalcitonin (r = 0.29; p = 0.022). After 24 months CCA-IMT correlated with AOPP (r = -0.30; p = 0.017). The independent factor of CCA-IMT progression after 24 months of observation was only CACS (delta CACS beta = 0.49). From the performed study, we can conclude that exacerbation of atherosclerosis and calcification in the circulatory system of patients treated with maintenance hemodialyses depends on microinflammation and oxidative stress. Reasonable tools for diagnostic algorithm estimation of atherosclerosis advancement in this group of patients are non-invasive, visual diagnostic techniques such as MSCT and ultrasonography.
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PMID:[Influence of microinflammation and oxidative stress on atherosclerosis progression and calcifications in cardiovascular system of hemodialyzed patients during two years follow-up]. 1794 65

Vascular smooth muscle cells (VSMCs), unlike other muscle cells, do not terminally differentiate. In response to injury, VSMCs change phenotype, proliferate, and migrate as part of the repair process. Dysregulation of this plasticity program contributes to the pathogenesis of several vascular disorders, such as atherosclerosis, restenosis, and hypertension. The discovery of mutations in the gene encoding BMPRII, the type II subunit of the receptor for bone morphogenetic proteins (BMPs), in patients with pulmonary arterial hypertension (PAH) provided an indication that BMP signaling may affect the homeostasis of VSMCs and their phenotype modulation. Here we report that BMP signaling potently induces SMC-specific genes in pluripotent cells and prevents dedifferentiation of arterial SMCs. The BMP-induced phenotype switch requires intact RhoA/ROCK signaling but is not blocked by inhibitors of the TGFbeta and PI3K/Akt pathways. Furthermore, nuclear localization and recruitment of the myocardin-related transcription factors (MRTF-A and MRTF-B) to a smooth muscle alpha-actin promoter is observed in response to BMP treatment. Thus, BMP signaling modulates VSMC phenotype via cross-talk with the RhoA/MRTFs pathway, and may contribute to the development of the pathological characteristics observed in patients with PAH and other obliterative vascular diseases.
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PMID:Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors. 1794 37

A broad variety of microbes are present in atherosclerotic plaques and chronic bacterial infection increases the risk of atherosclerosis by mechanisms that have remained vague. One possible mechanism is that bacteria or bacterial products activate plaque mast cells that are known to participate in the pathogenesis of atherosclerosis. Here, we show by real-time PCR analysis and ELISA that Chlamydia pneumoniae (Cpn) and a periodontal pathogen, Aggregatibacter actinomycetemcomitans (Aa), both induce a time and concentration-dependent expression and secretion of interleukin 8 (IL-8), tumour necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) by cultured human peripheral blood-derived mast cells, but not anti-inflammatory molecules, such as IL-10 or transforming growth factor beta 1 (TGF-beta 1). The IL-8 and MCP-1 responses were immediate, whereas the onset of TNF-alpha secretion was delayed. The Cpn-mediated pro-inflammatory effect was attenuated when the bacteria were inactivated by UV-treatment. Human monocyte-derived macrophages that were pre-infected with Cpn also induced a significant pro-inflammatory response in human mast cells, both in cocultures and when preconditioned media from Cpn-infected macrophages were used. Intranasal and intravenous administration of live Cpn and Aa, respectively induced an accumulation of activated mast cells in the aortic sinus of apolipoprotein E-deficient mice, however, with varying responses in the systemic levels of lipopolysaccharide (LPS) and TNF-alpha. Pro-atherogenic Cpn and Aa induce a pro-inflammatory response in cultured human connective tissue-type mast cells and activation of mouse aortic mast cells in vivo.
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PMID:Pro-atherogenic lung and oral pathogens induce an inflammatory response in human and mouse mast cells. 1829 59

Alternatively activated (M2) macrophages regulate steady state-, cancer-, and inflammation-related tissue remodeling. They are induced by Th2-cytokines and glucocorticoids (GC). The responsiveness of mature macrophages to TGF-beta, a cytokine involved in inflammation, cancer, and atherosclerosis, is currently controversial. Recently, we demonstrated that IL-17 receptor B is up-regulated in human monocyte-derived macrophages differentiated in the presence of Th2 cytokines IL-4 and TGF-beta1. In this study, we show that mature human macrophages differentiated in the presence of IL-4, and dexamethasone (M2(IL-4/GC)) but not M2(IL-4) responds to TGF-beta1 which induced a gene expression program comprising 111 genes including transcriptional/signaling regulators (ID3 and RGS1), immune modulators (ALOX5AP and IL-17 receptor B) and atherosclerosis-related genes (ALOX5AP, ORL1, APOC1, APOC2, and APOE). Analysis of molecular mechanism underlying GC/TGF-beta cooperation revealed that surface expression of TGF-betaRII was high in M2(GC) and M2(IL-4/GC), but absent from M2(IL-4), whereas the expression of TGF-betaRI/II mRNA, TGF-betaRII total protein, and surface expression of TGF-betaRIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF-betaRII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF-beta1-treated M2(IL-4/GC) was due to insufficient activity of negative feedback mechanism what can be explained by up-regulation of SIRT1, a negative regulator of Smad7, and the retention of TGF-betaRII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF-beta by GC-induced surface expression of TGF-betaRII activate in response to TGF-beta1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion.
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PMID:Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II. 1845 74

There is increasing evidence that TGF-beta family member cytokine bone morphogenetic protein (BMP)-4 plays different pathophysiological roles in the pulmonary and systemic circulation. Upregulation of BMP-4 has been linked to atherosclerosis and hypertension in the systemic circulation, whereas disruption of BMP-4 signaling is associated with the development of pulmonary hypertension. To test the hypothesis that BMP-4 elicits differential effects in the pulmonary and systemic circulation, we compared the prooxidant and proinflammatory effects of BMP-4 in cultured human coronary arterial endothelial cells (CAECs) and pulmonary arterial endothelial cells (PAECs). We found that BMP-4 (from 0.3 to 10 ng/ml) in CAECs increased O(2)(*-) and H(2)O(2) generation, induced NF-kappaB activation, upregulated ICAM-1, and induced monocyte adhesiveness to ECs. In contrast, BMP-4 failed to induce oxidative stress or endothelial activation in PAECs. Also, BMP-4 treatment impaired acetylcholine-induced relaxation and increased O(2)(*-) production in cultured rat carotid arteries, whereas cultured rat pulmonary arteries were protected from these adverse effects of BMP-4. Thus, we propose that BMP-4 exerts prooxidant, prohypertensive, and proinflammatory effects only in the systemic circulation, whereas pulmonary arteries are protected from these adverse effects of BMP-4. The vascular bed-specific endothelial effects of BMP-4 are likely to contribute to its differential pathophysiological role in the systemic and pulmonary circulation.
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PMID:Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells. 1853 60

A role of ACE I/D polymorphism in the pathogenesis of abdominal aortic aneurysm (AAA) has been demonstrated, possibly due to the effect of angiotensin II on vascular tissue remodelling. Angiotensin II exerts profibrogenic effects through the local induction of TGF-beta. Dysregulated TGF-beta signalling may result from mutations in TGFBR1 and TGFBR2 genes, thus resulting in degenerative changes in the vessel wall. We performed a case-control study in order to investigate the role of TGFBR1 9A6A polymorphism as predisposing factor to AAA per se, and in the presence of ACE DD and AT1R 1166 CC genotypes in 201 AAA patients (mean age+/-S.D., 71.5+/-6.9) referred to the Unit of Vascular Surgery of the University of Florence, compared with 252 healthy controls (mean age+/-S.D., 70.6+/-8.6). A significant difference in genotype distribution and allele frequency between patients and controls was found for ACE, but not for AT1R and TGFBR1 polymorphisms. At univariate analysis a significant association between ACE DD, but not AT1R CC and TGFBR1 6A allele, and the susceptibility to the disease was found [ACE DD OR=1.86 (95% CI 1.26-2.76), p=0.002]. After adjustment for age, gender, traditional cardiovascular risk factors, and CAD, PAD and CVD, ACE DD genotype still affected the susceptibility to AAA [OR=2.13 (95% CI 1.06-4.28), p=0.03], and the contemporary presence of ACE DD genotype and TGFBR1 6A allele, increased the predisposition to the disease [OR=5.09 (95% CI 1.44-18.02), p=0.01]. This study, which demonstrates an interaction between ACE and TGFBR1 genes in predisposing to AAA, may provide further information on the mechanisms contributing to AAA susceptibility, and offer a topic for future larger studies.
Atherosclerosis 2009 Jan
PMID:ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm. 1855 62

The growth arrest-specific gene 6 (Gas6) plays a role in pro-atherogenic processes such as endothelial and leukocyte activation, smooth muscle cell migration and thrombosis, but its role in atherosclerosis remains uninvestigated. Here, we report that Gas6 is expressed in all stages of human and mouse atherosclerosis, in plaque endothelial cells, smooth muscle cells and macrophages. Gas6 expression is most abundant in lesions containing high amounts of macrophages, ie thin fibrous cap atheroma and ruptured plaque. Genetic loss of Gas6 does not affect the number and size of initial and advanced plaques in ApoE(-/-) mice, but alters its plaque composition. Compared to Gas6(+/+): ApoE(-/-) mice, initial and advanced plaques of Gas6(-/-): ApoE(-/-) mice contained more smooth muscle cells and more collagen and developed smaller lipid cores, while the expression of TGFbeta was increased. In addition, fewer macrophages were found in advanced plaques of Gas6(-/-): ApoE(-/-) mice. Hence, loss of Gas6 promotes the formation of more stable atherosclerotic lesions by increasing plaque fibrosis and by attenuating plaque inflammation. These findings identify a role for Gas6 in plaque composition and stability.
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PMID:Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis. 1857 Jan 89


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