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)

Lipids, monocytes, and arterial wall cells are primary components involved in atherogenesis. Using the inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H), which have been extensively studied as models of the genetic control of diet-induced atherosclerosis, we examined which of these components determine genetic susceptibility. To test whether dietary responsiveness is involved, a congenic strain of C3H carrying an apoE-null allele (apoE(-/-)) was constructed. Although C3H.apoE(-/-) mice had higher plasma cholesterol levels, they developed much smaller lesions than their B6.apoE(-/-) counterpart on either chow or Western diets. Reciprocal bone marrow transplantation between the strains, with congenics carrying the same H-2 haplotype, was performed to examine the role of monocytes. The atherosclerosis susceptibility was not altered in the recipient mice, indicating that variations in monocyte function were not involved. Endothelial cells isolated from the aorta of B6 mice exhibited a dramatic induction of monocyte chemotactic protein-1, macrophage colony-stimulating factor, vascular cell adhesion molecule-1, and heme oxygenase-1 in response to minimally modified LDL, whereas endothelial cells from C3H mice showed little or no induction. In a set of recombinant inbred strains derived from the B6 and C3H parental strains, endothelial responses to minimally modified LDL cosegregated with aortic lesion size. These data provide strong evidence that endothelial cells, but not monocytes or plasma lipid levels, account for the difference in susceptibility to atherosclerosis between the 2 mouse strains.
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PMID:Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model: evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism. 1082 28

Atherosclerosis is an inflammatory disease. Platelet-endothelium interaction plays an important role in the pathophysiology of atherogenesis. We investigated the role of activated platelets for secretion of interleukin (IL)-1beta, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha and expression of intercellular adhesion molecule (ICAM)-1 on endothelial cells. Human umbilical vein endothelial cells (HUVEC) were incubated with non-stimulated or ADP-activated platelets for 6 hr. Secretion of interleukin (IL)-1beta, MCP-1 and MIP-1alpha and surface expression of ICAM-1 were measured by ELISA and flow cytometry. In the presence of activated platelets, the secretion of IL-1beta, MCP-1, and MIP-1alpha and surface expression of ICAM-1 were significantly increased compared with non-activated platelets. The present study shows that activated platelets may contribute to expression of various inflammatory mediators on endothelial cells.
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PMID:Activated platelets induce secretion of interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha and surface expression of intercellular adhesion molecule-1 on cultured endothelial cells. 1089 67

The beneficial effects of statins on the reduction of cardiovascular events has been partly attributed to their anti-inflammatory properties. In the complex of the different pathogenetic events leading to atherosclerosis, recent data suggest a central role of monocyte chemotactic protein-1 (MCP-1), because mice knock-out for MCP-1 or its receptor CC-chemokine receptor 2 were considerably resistant to plaque formation. In this study we investigated the effect of different statins on in vitro and in vivo production of MCP-1. Lovastatin and simvastatin caused a dose-dependent inhibition of MCP-1 production in peripheral blood mononuclear cells exposed to lipopolysaccharide or inactivated Streptococcus hemoliticus and in human endothelial cells exposed to interleukin-1beta. The addition of mevalonate overrode the inhibitory effect of statins indicating that mevalonate-derived products are important for chemokine production. The in vivo anti-inflammatory effect of statins was investigated using the mouse air-pouch model of local inflammation. Lovastatin and pravastatin were orally administered to mice according to a treatment schedule that significantly inhibited the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity without affecting total blood cholesterol. At the dose of 10 mg/kg, lovastatin and pravastatin reduced by approximately 50% the lipopolysaccharide-induced leukocytes recruitment and the exudate MCP-1 production. In conclusion, statins, by inhibiting mevalonate-derived products, reduced both in vitro and in vivo the production of chemokines involved in leukocyte migration, and this effect is unrelated to their cholesterol-lowering action.
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PMID:Inhibition of monocyte chemotactic protein-1 synthesis by statins. 1090 55

Antioxidants that prevent low density lipoproteins (LDL) from oxidation may inhibit atherosclerosis and post-angioplasty restenosis. Salvia miltiorrhiza (SM) has been shown to inhibit LDL oxidation and reduce atherosclerosis in cholesterol-fed rabbits. The effects of SM on neointimal hyperplasia and monocyte chemotactic protein-1 (MCP-1) expression after balloon injury were studied. Male New Zealand white rabbits were fed a 2% cholesterol diet together with daily SM (4.8 gm/kg body wt.) treatment (SM; n=10) or without SM as a control (C; n=9) for 6 weeks. Probucol-treated (0.6 gm/kg body wt.) rabbits (P; n=9) were used as a positive control group. A balloon injury of the abdominal aorta was performed at the end of the third week. Aortas were harvested at the end of 6 weeks. The plasma cholesterol levels were lowered in SM group. The neointimal hyperplasia in abdominal aortas was significantly inhibited in SM group [neointima/media area ratio: 0.63+/-0.05 (SM) versus 0.78+/-0.05 (C); P < 0.05] and in P group [0.45+/-0.02 (P) versus 0.78+/-0.05 (C); P < 0.05] when compared with C group. SM treatment significantly reduced MCP-1 mRNA and protein expression in balloon-injured abdominal aorta. These inhibitory effects on intimal response after balloon injury might be attributed to antioxidant capacity and cholesterol lowering effect of SM. SM treatment may offer some protection against post-angioplasty restenosis.
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PMID:Salvia miltiorrhiza inhibits intimal hyperplasia and monocyte chemotactic protein-1 expression after balloon injury in cholesterol-fed rabbits. 1159 16

Hematein is a compound isolated from Caesalpinia sappan that has been used in oriental medicine as both an analgesic and an anti-inflammatory agent. In this study, we examined the anti-atherogenic potential of hematein using cholesterol-fed New Zealand White (NZW) rabbits. NZW rabbits were divided into a hematein-supplemented (0.05% in diet) group (n=6), a probucol-supplemented (0.25% in diet) group (n=6), and a control group (n=6). After 8 weeks of treatments, the extent of the atherosclerotic lesions was significantly reduced in the hematein-supplemented group and the probucol-supplemented group without changing plasma lipoprotein levels. Hematein and probucol prevented the up-regulation of the vascular cell adhesion molecule-1 (VCAM-1) expression on the descending aorta induced by cholesterol diet. In culture, hematein also significantly inhibited the secretion of soluble VCAM-1 and of monocyte chemotactic protein-1 (MCP-1) respectively induced by tumor necrotic factor alpha (TNF-alpha) and mildly oxidized low density lipoprotein in human umbilical vein endothelial cell (HUVEC) culture. Also, hematein inhibited monocyte adhesion to endothelial cell and the activation of NF-kappaB in HUVECs stimulated with TNF-alpha. The results of the present study suggest that the anti-atherogenic effect of hematein is not related to control of the plasma lipid profile but probably related to the inhibition of VCAM-1 and MCP-1 expression resulting in an amelioration of lesion development in the rabbit.
Atherosclerosis 2001 Nov
PMID:Dietary hematein ameliorates fatty streak lesions in the rabbit by the possible mechanism of reducing VCAM-1 and MCP-1 expression. 1168 2

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely used in the treatment of dyslipemias and have shown beneficial effects in primary and secondary prevention of cardiovascular diseases. There is new information that seems to suggest that the beneficial effects observed may not be solely attributable to plasma cholesterol reduction. Our objective has been to evaluate the effect of two statins at similar dose, although unequivalent plasma lipid lowering potential, on vessel wall expression of two proteins involved in atherosclerotic lesion progression. We have studied the effects of treatment on vessel wall expression of monocyte chemotactic protein-1 (MCP-1) and the inducible form of nitric oxide synthase (NOS II). Atherosclerosis was induced in pigs by feeding a high cholesterol and saturated fatty acid diet for 50 days. Mild atherosclerotic lesions were found at this early stage of induction. Animals were simultaneously treated with atorvastatin (3 mg/kg/day), pravastatin (3 mg/kg/day) or placebo. Non-HDL-cholesterol levels induced by diet were reduced in the atorvastatin-treated group (63+/-8%, P=0.03) and not as much in the pravastatin treated group (44+/-3, P=0.08). The average MCP-1 expression in carotid, femoral and thoracic aorta was significantly reduced with both statins by 37% (P<0.05), while NOS II expression was unaffected. Therefore, vascular MCP-1 expression was downregulated by statins regardless of their lipid lowering potential and lipo/hydrophilic characteristics. Early downregulation of MCP-1 could attenuate the inflammation within the vascular wall and prevent the development of atherosclerotic lesions.
Atherosclerosis 2001 Nov
PMID:HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels. 1168 3

Porphyromonas gingivalis is an oral pathogen that has recently been associated with chronic inflammatory diseases such as atherosclerosis. The strength of the epidemiological associations of P. gingivalis with atherosclerosis can be increased by the demonstration that P. gingivalis can initiate and sustain growth in human vascular cells. We previously established that P. gingivalis can invade aortic, heart, and human umbilical vein endothelial cells (HUVEC), that fimbriae are required for invasion of endothelial cells, and that fimbrillin peptides can induce the expression of the chemokines interleukin 8 and monocyte chemotactic protein. In this study, we examined the expression of surface-associated cell adhesion molecules on endothelial cells in response to P. gingivalis infection by fluorescence-activated cell sorting FACS analysis and confocal microscopy. Coculture of HUVEC with P. gingivalis strain 381 or A7436 resulted in the induction in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P- and E-selectins, which was maximal at 48 h postinfection. In contrast, we did not observe induction of ICAM-1, VCAM-1, or P- or E-selectin expression in HUVEC cultured with the noninvasive P. gingivalis fimA mutant DPG3 or when P. gingivalis was incubated with fimbrillin peptide-specific anti-sera prior to the addition to HUVEC. Furthermore, the addition of a peptide corresponding to the N-terminal domain of fimbrillin to HUVEC resulted in an increase in ICAM-1, VCAM-1, and P- and E-selectins, which was maximal at 48 h and similar to that observed for live P. gingivalis. Treatment of P. gingivalis-infected HUVEC with cytochalsin D, which prevented P. gingivalis invasion, also resulted in the inhibition of ICAM-1, VCAM-1, or P- and E-selectin expression. Taken together, these results indicate that active P. gingivalis invasion of HUVEC mediated via the major fimbriae stimulates surface-associated cell adhesion molecule expression. Stimulation of adhesion molecules involved in the recruitment of leukocytes to sites of inflammation by P. gingivalis may play a role in the pathogenesis of systemic inflammatory diseases associated with this microorganism, including atherosclerosis.
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PMID:Fimbria-dependent activation of cell adhesion molecule expression in Porphyromonas gingivalis-infected endothelial cells. 1174 91

Atherosclerosis and its major clinical manifestation, coronary heart disease, is and will remain the main cause of mortality. Reviews on this subject dealt with factors that enhance development of atherosclerosis. This review deals with a new facet, that some individuals are less prone to develop atherosclerosis: (1) despite high cholesterol intake or (2) despite hypercholesterolemia with elevated low-density lipoprotein cholesterol (LDL-C) levels. The variability of response of plasma cholesterol to dietary intake was shown to be regulated by liver x receptor (LXR) that determines the rate of intestinal cholesterol absorption through the ATP-binding cassette (ABC) gene family. Other gene products, such as apolipoprotein-E (apo-E), scavenger receptor-B1 (SR-B1) and acyl coenzyme: cholesterol acyltransferase-2 (ACAT-2) affect cholesterol absorption also. The role of a genetic background for relative resistance to atherosclerosis is highlighted by subjects with familial hypercholesterolemia in whom high plasma cholesterol levels has not curtailed their expected life span. Studies in animals have shown that resistance to atherosclerosis in spite of hypercholesterolemia is affected by factors such as high-density lipoprotein (HDL) phospholipids that enhance reverse cholesterol transport, non-responsiveness to induction or lack of monocyte chemotactic protein-1 (MCP-1), C-C chemokine receptor 2 (CCR2), macrophage colony stimulating factor (MCSF), or vascular cell adhesion molecule-1 (VCAM-1). Since macrophages have been regarded as pro- or anti-atherogenic, evidence was collated that the high activity of scavenger receptors may contribute towards resistance to atherosclerosis if accompanied by adequate amounts of apo-E for cholesterol removal.
Atherosclerosis 2002 Jan
PMID:Is there a genetic basis for resistance to atherosclerosis? 1175 17

1. In a previous study, we showed that magnolol, a potent antioxidant derived from a Chinese herb, attenuates monocyte chemotactic protein-1 (MCP-1) expression and intimal hyperplasia in the balloon-injured aorta of cholesterol-fed rabbits. Expression of cell adhesion molecules by the arterial endothelium and the attachment of leukocytes to the endothelium may play a major role in atherosclerosis. In the present study, the effects of magnolol on the expression of endothelial-leukocyte adhesion molecules and the activation of nuclear factor kappa B (NF-kappa B) in tumour necrosis factor-alpha (TNF-alpha)-treated human aortic endothelial cells (HAECs) were investigated. 2. Pretreatment of HAECs with magnolol (5 microM) significantly suppressed the TNF-alpha-induced expression of vascular cell adhesion molecule-1 (VCAM-1) (64.8+/-1.9%), but had no effect on the expression of intercellular cell adhesion molecule-1 and endothelial cell selectin. 3. Magnolol (5 and 10 microM) significantly reduced the binding of the human monocytic cell line, U937, to TNF-alpha-stimulated HAECs (58.4 and 56.4% inhibition, respectively). Gel shift assays using the (32)P-labelled NF-kappa B consensus sequence as probe showed that magnolol pretreatment reduced the density of the shifted bands seen after TNF-alpha-induced activation. Immunoblot analysis and immunofluorescence staining of nuclear extracts demonstrated a 58% reduction in the amount of NF-kappa B p65 in the nuclei in magnolol-treated HAECs. Magnolol also attenuated intracellular H(2)O(2) generation in both control and TNF-alpha treated HAECs. 4. Furthermore, in vivo, magnolol attenuates the intimal thickening and TNF-alpha and VCAM-1 protein expression seen in the thoracic aortas of cholesterol-fed rabbits. 5. Taken together, these data demonstrate that magnolol inhibits TNF-alpha-induced nuclear translocation of NF-kappa B p65 and thereby suppresses expression of VCAM-1, resulting in reduced adhesion of leukocytes. These results suggest that magnolol has anti-inflammatory properties and may play important roles in the prevention of atherosclerosis and inflammatory responses in vivo.
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PMID:Magnolol attenuates VCAM-1 expression in vitro in TNF-alpha-treated human aortic endothelial cells and in vivo in the aorta of cholesterol-fed rabbits. 1178 78

Antagonists of the renin-angiotensin system, such as angiotensin type 1 (AT(1)) receptor inhibitors and angiotensin-converting enzyme inhibitors, are becoming increasingly popular agents in treating patients with systemic hypertension and minimizing organ damage. In the present study, we compared the effects of eprosartan, an AT(1) receptor inhibitor, with the diuretic hydrochlorothiazide in a group of newly diagnosed hypertensive patients with multiple risk factors for atherosclerosis. The subjects were monitored and tested at 0 and 4 weeks to determine their individual effects on vascular and inflammatory markers. Although blood pressure reduction was comparable between the 2 agents, there were notable differences in their effects on markers of inflammation and oxidation. We observed a 28% reduction in neutrophil superoxide anion generating capacity, a 34% reduction in soluble monocyte chemotactic protein-1, and a 35% reduction in soluble vascular cell adhesion molecule with eprosartan therapy (all p <0.05 from the start of therapy). In addition, eprosartan showed further benefit in its ability to increase low-density lipoprotein oxidation lag time, suggesting an increased resistance to oxidation and/or modification of low-density lipoprotein. Although hydrochlorothiazide was effective in blood pressure reduction, there were no significant changes in any of the above parameters after 4 weeks of treatment. These findings suggest that eprosartan, an AT(1) receptor inhibitor, effectively reduces systemic blood pressure and, compared with hydrochlorothiazide, suggests additional benefits in the vasculature by inhibiting mechanisms of inflammation and oxidation.
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PMID:Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin-angiotensin system antagonists, oxidation, and inflammation). 1189 10


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