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)

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon-gamma (IFN-gamma) contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule-1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the IFN-gamma-induced extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and IFN-gamma, ICAM-1 was expressed at a lower level than in cells treated with IFN-gamma alone. However, lovastatin does not reduce TNF-alpha induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and IFN-gamma. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the IFN-gamma activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit IFN-gamma-mediated induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the IFN-gamma-mediated phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. TNF-alpha does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting IFN-gamma action in atherosclerotic process
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PMID:Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. 1252 87

Increased interaction of monocytes with vascular cells is linked to the development and progression of atherosclerosis in patients with diabetes. One major determinant of increased monocyte binding to vascular cells could be oxidative stress. Given the free-radical scavenging properties of gliclazide, we evaluated the ex vivo and in vitro effects of this drug on human monocyte binding to endothelial cells and smooth muscle cells (SMCs). Short-term administration of gliclazide to patients with type 2 diabetes decreases plasma lipid peroxides and lowers the enhanced adhesion of diabetic monocytes to cultured endothelial cells observed before gliclazide treatment. Gliclazide (10 microg/ml) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to cultured endothelial cells. The suppressive effect of gliclazide on AGE-induced monocyte adhesion to endothelium involves a reduction of cell adhesion molecule mRNA and protein expression and an inhibition of NF-kappaB activation. Gliclazide also inhibits oxLDL-induced monocyte adhesion to cultured human aortic smooth muscle cells (HASMCs). Furthermore, treatment of HASMCs with gliclazide results in a marked decrease in oxLDL-induced monocyte chemoattractant protein-1 expression, both at the gene and protein levels. These results suggest that gliclazide, at concentrations in the therapeutic range (5-10 microg/ml), by its ability to decrease monocyte-vascular cell interactions could reduce monocyte accumulation in the atherosclerotic plaque and thereby contribute to attenuate the sustained inflammatory process that occurs in the vessel wall. These findings suggest that treatment of diabetic patients with gliclazide may prevent or retard the development of vascular disturbances associated with diabetes.
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PMID:Monocyte adhesion in diabetic angiopathy: effects of free-radical scavenging. 1262 65

Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. The aim of this study was to assess the effects of a 6-month treatment with simvastatin (10 mg at bedtime) on markers of endothelial cell injury in 12 hypercholesterolemic CAPD patients. Cholesterol and low-density lipoprotein cholesterol fell significantly after 1 month of therapy. Simvastatin treatment significantly decreased concentrations of vascular cell adhesion molecule and intracellular adhesion molecule after 3 and 6 months of the therapy, respectively. Thrombomodulin decreased significantly after 6 months of the treatment, whereas von Willebrand's factor, P-selectin and E-selectin remained unaltered during simvastatin therapy. Simvastatin, an effective hypolipemic agent, favorably affects endothelial function and may potentially slow the progression of atherosclerosis and confer protection from thrombotic complications in patients with hypercholesterolemia undergoing CAPD.
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PMID:Simvastatin and markers of endothelial function in patients undergoing continuous ambulatory peritoneal dialysis. 1263 64

Viral infection of the vascular wall cellular elements is involved in development of several pathophysiological events, including vasculitis, transplant rejection, and atherosclerosis. Previously, we have shown that cultured human vascular endothelial cells (ECs) may be effectively infected with herpes simplex type I virus (HSV-1), and this cultural model could be a useful tool for the explanation of many aspects of viral disease. In this study, we investigated the effects of conditioned media (CM) of peripheral blood mononuclear cells (PBMCs) on HSV-1 reproduction and cell adhesion molecule expression in cultured ECs. PBMC-CM induced the delay of virus reproduction or inhibition of virus reproduction. Effects of CM correlated with multiplicity of infection used for EC, time of PBMC contact with infected and glutaraldehyde-fixed endothelium, and the level of IFNs and cytokine production. Passages of and CM-treated and infected cells without signs of virus reproduction were, sometimes, followed by virus reactivation. However, at a low level of infection of CM-treated ECs the virus reactivation was not observed even after 2-3 cell passages. Neutralizing antibodies against IFN-alpha, IFN-gamma, and TNF-alpha, used separately or together, significantly abrogated the delaying and/or inhibiting action of CM. Additionally, PBMC-CM significantly increased the expression of ICAM-1 and VCAM-1 on cultured ECs. The strongest cell activation was induced by CM obtained from PBMCs co-incubated with virus-infected endothelium. Obtained results suggest that primed leukocytes produce soluble factors with either anti-viral or pro-inflammatory activity, and the effect of PBMC-CM may have a bi-directional action. On the one hand, due to production of interferons and several cytokines CM sets up HSV-1 latency or virus elimination from cultured cells. On the other, the same cytokines act on infected and/or neighboring ECs and initiate the cascade of inflammatory reactions in the vascular wall.
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PMID:Herpes simplex type I virus infected human vascular endothelial cells induce the production of anti-viral and proinflammatory factors by peripheral blood leukocytes in vitro. 1268 53

Atherosclerosis is now viewed as an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions, including oscillatory shear stress (OS), in branched arteries. In contrast, the arterial regions exposed to laminar shear (LS) are relatively lesion-free. The mechanisms underlying the opposite effects of OS and LS on the inflammatory and atherogenic processes are not clearly understood. Here, through DNA microarrays, protein expression, and functional studies, we identify bone morphogenic protein 4 (BMP4) as a mechanosensitive and pro-inflammatory gene product. Exposing endothelial cells to OS increased BMP4 protein expression, whereas LS decreased it. In addition, we found BMP4 expression only in the selective patches of endothelial cells overlying foam cell lesions in human coronary arteries. The same endothelial patches also expressed higher levels of intercellular cell adhesion molecule-1 (ICAM-1) protein compared with those of non-diseased areas. Functionally, we show that OS and BMP4 induced ICAM-1 expression and monocyte adhesion by a NFkappaB-dependent mechanism. We suggest that BMP4 is a mechanosensitive, inflammatory factor playing a critical role in early steps of atherogenesis in the lesion-prone areas.
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PMID:Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. 1276 66

Platelet endothelial cell adhesion molecule (PECAM-1) is a member of the superfamily of immunoglobulins. This cell adhesion molecule has been implicated to mediate the adhesion and trans-endothelial migration of T lymphocytes/monocytes into the vascular wall, a critical step in the initiation of atherogenesis. Current thinking, however, posits that PECAM-1 by virtue of being a scaffolding molecule may well play a role in several signal transduction reactions. As a consequence, this cell adhesion molecule may be responsible for several biological and pathophysiological functions such as thrombosis, and inflammation. Evidence has also been put forward for a potential role of PECAM-1 in apoptosis and atherosclerosis. This article focuses on the structure of PECAM-1 and its role in intracellular signaling and implications in health and disease.
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PMID:Platelet endothelial cell adhesion molecule in cell signaling and thrombosis. 1461 65

CAP37, a neutrophil-derived protein, originally identified for its antimicrobial activity is now known to have strong immunoregulatory effects on host cells. Recently, we described its expression and localization within the vascular endothelium associated with atherosclerotic plaques. Since CAP37 is a potent activator of endothelial cells and monocytes, two of the key cellular components of the atherosclerotic plaque, this study was undertaken to determine whether CAP37 had functional effects on smooth muscle cells another important cellular participant in atherosclerosis. Sections from atherosclerotic lesions were stained for the presence of CAP37 and smooth muscle cell alpha actin. The effect of CAP37 on aorta smooth muscle cell migration and proliferation was investigated and the upregulation of adhesion molecules was determined. Immunocytochemistry indicated that CAP37 was present in a subset of smooth muscle cells within atherosclerotic lesions, but was absent in normal vessels. Flow cytometry using double labeling for the proliferation marker Ki-67 and CAP37 demonstrates that CAP37 is mainly expressed in proliferating smooth muscle cells. We show that CAP37 supports migration and proliferation of smooth muscle cells in vitro. Furthermore, CAP37-treated smooth muscle cells expressed higher levels of the cell adhesion molecule ICAM-1 when compared with untreated cells. We suggest that due to its localization to atherosclerotic plaques and its ability to modulate smooth muscle cells, CAP37 may play a role in the progression of this disease.
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PMID:Functional modulation of smooth muscle cells by the inflammatory mediator CAP37. 1502 Feb 8

In regions of a vessel that experience low shear stress and reversing flow patterns, early features in the pathogenesis of atherosclerosis include the accumulation of oxidized LDL (OxLDL) and adhesion of monocytes to endothelial cells (EC). Here we investigated the hypothesis that low shear stress (2 dyn/cm2) and OxLDL are synergistic for enhanced expression of vascular cell adhesion molecule (VCAM-1) and human aortic endothelial cell (HAEC)-monocyte adhesion. This study shows low shear stress can significantly reduce IkappaBalpha levels, activate NF-kappaB, increase the expression of VCAM-1 in HAEC and binding of monocytes. OxLDL itself cannot significantly increase the expression of VCAM-1 in HAEC and binding of monocytes, but through activation of NF-kappaB and degradation of IkappaBalpha induced by low shear stress it can significantly enhance VCAM-1 expression and monocyte adhesion, over that in unmodified LDL or control. These results suggest that low shear stress can regulate monocyte adhesion to oxidized lipid-induced endothelial cells via an IkappaBalpha-dependent pathway, and that low shear stress together with OxLDL may likely play an important role in atherogenesis.
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PMID:Low shear stress regulates monocyte adhesion to oxidized lipid-induced endothelial cells via an IkappaBalpha dependent pathway. 1509 Jun 81

Early stages of atherogenesis are characterized by the overexpression of cell adhesion molecules with the subsequent accumulation of macrophages, smooth muscle cells and proliferation of extracellular matrix in arterial intima. The quantification of atherogenic changes is necessary for the objective evaluation of the atherogenic process. The purpose of this study was to introduce stereological methods that may be used for the quantification of immunohistochemical staining, namely intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four New Zealand White rabbits were subdivided into the three groups. Eighteen rabbits received a 0.4% cholesterol diet for 1, 2 and 3 months, respectively. Stereological principles of the systematic uniform random sampling and the point-counting method were applied for the quantification. Stereological analysis showed that VCAM-1 and ICAM-1 were upregulated during the consumption of high cholesterol diet and that VCAM-1, but not ICAM-1, has a considerable role in the formation of early atherosclerotic lesions. Stereological methods proved to be useful for the quantification of immunohistochemistry and can be used for an objective characterization of atherogenic changes in atherosclerosis.
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PMID:Application of stereological methods for the quantification of VCAM-1 and ICAM-1 expression in early stages of rabbit atherogenesis. 1520 Feb 74

As an Old World nonhuman primate, baboons have been extensively used for research on dyslipidemia and atherogenesis. With increasing knowledge about the endothelium's role in the initiation and progression of atherosclerosis, the value of the baboon model can be increased by developing it for research on the role of dysfunctional endothelium in atherogenesis. Toward that goal, we have established and validated methods of isolating and culturing baboon femoral artery endothelial cells (BFAECs) and compared baboon endothelial cellular characteristics with those of humans. Our results indicated that baboon and human endothelial cells share similar growth and culture behaviors. As was the case for human endothelial cells, BFAECs responded to tumor necrosis factor (TNF)-alpha stimulation with increased expression of adhesion molecules (maximum increase for intracellular adhesion molecule (ICAM): 1.76 +/- 0.26-fold; vascular cell adhesion molecule (VCAM): 1.65 +/- 0.25-fold; E-selectin: 2.86 +/- 0.57-fold). However, BFAECs were hyporesponsive to lipopolysaccharide (LPS) (range, 0.25-20 microg/mL) in adhesion molecule expression, whereas 1 microg/mL LPS induced 2.14- to 3.71-fold increases in human endothelial cells. The differential responses to LPS were not related to TLR-2 and toll-like receptor (TLR)-4 expression on the cell surface. And baboon microvascular endothelial cells had similar features as BFAECs. We observed constitutive expression of interleukin (IL)-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)-1 in both human and baboon endothelial cells, and these cytokines were further induced by TNF-alpha and LPS. We also demonstrated that the responses to TNF-alpha or LPS varied among baboons maintained under the same dietary and environmental conditions, suggesting that response may be controlled by genetic factors.
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PMID:Comparative analysis of vascular endothelial cell activation by TNF-alpha and LPS in humans and baboons. 1521 Oct 29


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