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)

Vascular inflammation induced by the proinflammatory cytokine/NF-kappaB pathway is one of the key mechanisms in the development of neointimal hyperplasia. Accumulating evidence suggests that a recently identified chemokine, fractalkine, is involved in arterial inflammation and atherogenesis. However, no study has examined the expression of neointimal fractalkine and the effects of pharmacological agents on this process. The purposes of this study were to measure neointimal fractalkine expression in the rat carotid artery following balloon injury and to determine if alpha-lipoic acid (ALA) inhibits fractalkine expression and neointimal hyperplasia. Balloon injury of the rat carotid artery induced fractalkine expression in the medial as well as neointimal regions. ALA inhibited this expression and consequently prevented neoinitmal hyperplasia in a balloon-injured rat carotid artery. Additionally, ALA inhibited TNF-alpha-stimulated fractalkine expression in cultured vascular smooth muscle cells (VSMCs), a process which is mediated through the NF-kappaB pathway. In addition to fractalkine, ALA successfully inhibited TNF-alpha-stimulated expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 in cultured VSMCs. These data suggest that the cytokine-fractalkine system is involved in the pathogenesis of restenosis. The present study supports the possibility that ALA, which inhibits the NF-kappaB/fractalkine pathway, may be used to prevent neointimal hyperplasia after angioplasty or stenting.
Atherosclerosis 2006 Nov
PMID:Alpha-lipoic acid inhibits fractalkine expression and prevents neointimal hyperplasia after balloon injury in rat carotid artery. 1641 26

Magnolol (Mag), an active constituent isolated from the Chinese herb Hou p'u (Magnolia officinalis) has long been used to suppress inflammatory processes. Chronic inflammation is well known to be involved in vascular injuries such as atherosclerosis in which interleukin (IL)-6 may participate. Signal transducer and activator of transcription protein 3 (STAT3), a transcription factor involved in inflammation and the cell cycle, is activated by IL-6. In this study, we evaluated whether Mag can serve as an anti-inflammatory agent during endothelial injuries. The effects of Mag on IL-6-induced STAT3 activation and downstream target gene induction in endothelial cells (ECs) were examined. Pretreatment of ECs with Mag dose dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pretreatment of these ECs dose dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs). An electrophoretic mobility shift assay (EMSA) revealed that Mag treatment significantly reduced STAT3 binding to the IRE region. Consistently, Mag treatment markedly inhibited ICAM-1 expression on the endothelial surface. As a result, reduced monocyte adhesion to IL-6-activated ECs was observed. Furthermore, Mag suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. In conclusion, our results indicate that Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis.
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PMID:Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells. 1652 Jul 48

The receptor for advanced glycation end products (RAGE) and its ligands have been implicated in the activation of oxidant stress and inflammatory pathways in vascular smooth muscle cells (VSMCs) leading to the initiation and augmentation of atherosclerosis. Here we report that non-receptor Src tyrosine kinase and the membrane protein caveolin-1 (Cav-1) play a key role in the activation of RAGE by S100B in VSMCs. S100B increased the activation of Src kinase and tyrosine phosphorylation of caveolin-1 in VSMCs. A RAGE-specific antibody blocked both these effects. An inhibitor of Src kinase, PP2, significantly blocked S100B-induced activation of Src kinase, mitogen-activated protein kinases, transcription factors NF-kappaB and STAT3, superoxide production, tyrosine phosphorylation of Cav-1, VSMC migration, and expression of the pro-inflammatory genes monocyte chemotactic protein-1 and interleukin-6. Cholesterol depletion also inhibited S100B-induced effects indicating the requirement for intact caveolae in RAGE-specific signaling. Nucleofection of either a Src dominant negative mutant, or a Cav-1 mutant lacking the scaffolding domain, or Cav-1 short hairpin RNA significantly reduced S100B-induced inflammatory gene expression in VSMCs. Furthermore, VSMCs derived from insulin-resistant and diabetic db/db mice displayed increased RAGE expression, Src activation, and migration compared with those from control db/+ mice. The RAGE antibody blocked enhanced migration in db/db cells. These studies demonstrate for the first time that, in VSMCs, Src kinase and Cav-1 play important roles in RAGE-mediated inflammatory gene expression and migration, key events associated with diabetic vascular complications.
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PMID:Key role of Src kinase in S100B-induced activation of the receptor for advanced glycation end products in vascular smooth muscle cells. 1655 28

Aldosterone is a mineralocorticoid hormone that plays an important role in regulating electrolyte balance and blood pressure and also participates in endothelial dysfunction. We evaluated the direct effect of aldosterone on human umbilical vein cells (HUVEC). Levels of eNOS phosphorylation by vascular endothelial growth factor were diminished, and the amount of NO produced in response to vascular endothelial growth factor measured as NO2+NO3 was significantly decreased in cells previously incubated with aldosterone. Incubation with aldosterone for 24 h dose-dependently increased Nox4 mRNA expression in HUVEC. Although NF-kappaB was not apparently activated by aldosterone, mRNA levels of vascular cell adhesion molecule-1, E-selectin, monocyte chemotactic protein-1, and intercellular adhesion molecule-1 in HUVEC were significantly increased after incubation with aldosterone. Thus, aldosterone directly causes the dysregulation of endothelial cell function, which may be partly responsible for high blood pressure and atherosclerosis.
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PMID:Aldosterone impairs vascular endothelial cell function. 1668 76

The reverse transcription polymerase chain reaction (RT-PCR) is one of the most useful molecular biology methods in opening the way to understanding of the mechanisms of atherosclerosis on the gene structure and/or expression level. We optimized this technique for assaying expression of the monocyte chemotactic protein type 1 (MCP-1) gene in rabbit aorta with respect to the temperature profile, yield to cycle number, interference of genomic DNA with the RNA matrix, and repeatability. Variability of expression of the constitutive GAPDH gene was also examined. The study was done in 18 New Zealand rabbits allocated to two groups and fed a standard chow for 2 (S1) or 3 (S2) months. The experiment ended with removal of part of the ascending rabbit aorta, from which RNA was isolated. The optimal temperature for binding of specific primers to the MCP-1 and GAPDH genes was 63 degrees C, and the optimal number of cycles for PCR amplification was 22 for MCP-1 and 26 for GAPDH. The GAPDH amplicon size was 465 base pairs in the presence or absence of reverse transcriptase showing contamination of the RNA matrix with genomic DNA. Repeatability of the RT-PCR method was 8.7%, and variability of expression of the GAPDH gene was 7.7%. Thus, RT-PCR adjusted for contaminating genomic DNA provides a reliable way of assaying expression of the MCP-1 gene in rabbit aorta.
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PMID:Optimized RT-PCR method for assaying expression of monocyte chemotactic protein type 1 (MCP-1) in rabbit aorta. 1678 99

Oxidative modification of LDL accumulated in the subendothelial space is a critical step in atherogenesis. Mouse strains C57BL/6 (B6) and BALB/c differ markedly in atherosclerosis susceptibility. We sought to determine whether variation of endothelial cells in the capacity to oxidize LDL or in response to minimally modified LDL (MM-LDL) constitutes a genetic component in atherosclerosis. LDL oxidation was assessed by measuring thiobarbituric acid-reactive substance (TBARS) production. Responses to MM-LDL were evaluated by examining induction of monocyte chemotactic protein-1, macrophage-colony stimulating factor, and vascular cell adhesion molecule-1. Both strains exhibited comparable endothelial responses to MM-LDL, whereas BALB/c mice had an increased rate of oxidizing LDL compared with B6 mice. To examine whether endothelial nitric oxide synthase (eNOS) contributed to the difference in LDL oxidation, cells were incubated with native LDL in the presence or absence of N(Omega)-nitro-l-arginine methyl ester (l-NAME), a specific NOS inhibitor. Although l-NAME significantly inhibited endothelial cell-mediated LDL oxidation, it failed to abolish the difference between the strains. In contrast, Baicalein, a specific 12/15 lipoxygenase inhibitor, abolished the difference in LDL oxidation. Thus, the paradoxical increase in LDL oxidation by endothelial cells is attributable to higher oxidant activity of 12/15-lipoxygenase in BALB/c mice and endothelial cells appear unlikely to be a source of the resistance to atherosclerosis.
Atherosclerosis 2007 Jun
PMID:Paradoxical increase in LDL oxidation by endothelial cells from an atherosclerosis-resistant mouse strain. 1691 36

Vascular inflammation induced by the proinflammatory cytokine/NF-kappaB pathway is one of the key mechanisms in the development of atherosclerosis. Peroxisome proliferators-activated receptor-gamma (PPARgamma) plays an important role in the prevention of arterial inflammation and formation of atherogenesis. Herein we examine the effects of a newly identified synthetic PPARgamma ligand, ascochlorin-6 (AS-6), on TNF-alpha-stimulated NF-kappaB activity and inflammatory molecule expression in vascular smooth muscle cells (VSMCs). AS-6 successfully inhibited TNF-alpha-stimulated NF-kappaB activity and inflammatory molecule expression, including vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and fractalkine (CX3CL1). Transient transfection with an [NF-kappaB]x4 luciferase reporter construct showed that AS-6 inhibition of TNF-alpha-stimulated NF-kappaB activation was PPARgamma-dependent. The effects of AS-6 on TNF-alpha-stimulated VCAM-1 and CX3CL1 expression were abolished in cells transfected with an adenovirus expressing dominant-negative PPARgamma and in cells treated with a PPARgamma specific inhibitor, GW9662, confirming again that the anti-inflammatory effect of AS-6 was PPARgamma-dependent. The inhibitory effects of AS-6 on TNF-alpha-stimulated inflammatory gene expression and NF-kappaB activation were more potent than those of rosiglitazone and pioglitazone. This study shows that AS-6 reduces the inflammatory response to TNF-alpha in VSMCs. The data suggest the possibility that AS-6 can be used to prevent the development and progression of atherosclerosis.
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PMID:The ascochlorin derivative, AS-6, inhibits TNF-alpha-induced adhesion molecule and chemokine expression in rat vascular smooth muscle cells. 1698 70

Early stages of atherosclerosis are commonly noted in youth. The present study was designed to examine the effects of lifestyle modification in 19 overweight children (age 8-17) who were placed on a high-fiber, low-fat diet in a 2-week residential program where food was provided ad libitum and daily exercise (2-2.5h) was performed. In each subject, pre- and post-intervention fasting blood was drawn to measure serum lipids, oxidative stress marker 8-isoprostaglandin F2alpha (8-iso-PGF2alpha) and generating enzyme myeloperoxidase (MPO), soluble intracellular adhesion molecule (sICAM)-1 and sE-selectin as indicators of endothelial activation, the inflammatory protein C-reactive protein (CRP) and total matrix metalloproteinase-9 (MMP-9). Using subject sera and human aortic endothelial cell (HAEC) culture systems, monocyte chemotactic protein-1 (MCP-1) production, as well as nitric oxide (NO), superoxide and hydrogen peroxide production were measured in vitro by fluorometric detection. After 2 weeks, significant reductions (p<0.05) in all serum lipids (except HDL cholesterol), 8-iso-PGF2alpha, MPO, sICAM-1, sE-selectin, CRP, MMP-9, and cellular MCP-1 production were noted. Additionally, there was a significant decrease in cultured, serum-stimulated HAEC production of superoxide and hydrogen peroxide, and a concomitant increase in NO production (all p<0.01), These results indicate amelioration of several traditional as well as novel factors associated with atherosclerosis after lifestyle modification, even in youth without documented disease.
Atherosclerosis 2007 Mar
PMID:Effect of a short-term diet and exercise intervention in youth on atherosclerotic risk factors. 1705 60

Atherosclerosis is an inflammatory response of the arterial wall to 'injury', which is prominently driven by inflammatory factors. Clopidogrel reduces early atherosclerosis, however, the role of clopidogrel in modulating inflammatory progression of atherosclerosis is less investigated. We wished to determine the effect of clopidogrel on progression of established atherosclerosis, vascular inflammatory factors and compared with that of aspirin and atorvastatin. Fifty male New Zealand white (NZW) rabbits were divided into five groups randomly including negative group. The rabbits were fed with a normal diet or a high cholesterol diet for 7 weeks. The right iliac artery of animals except negative group were balloon injured 1 week after initiation of the diet, then animals were treated with clopidogrel (4 mg/kg/day), aspirin (12 mg/kg/day), atorvastatin (2.5mg/kg/day) or placebo for 6 weeks. At the end of the study, the placebo (positive) group had significant progression of atherosclerosis compared with negative group. In contrast, clopidogrel, aspirin or atorvastatin treated rabbits showed a significant reduction in progression of atherosclerosis and decreased the levels of P-selection, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in serum and vascular wall. Among three drugs, the action of clopidogrel is the most powerful in decreasing the levels of inflammatory factors. These results suggest that in a rabbit atherosclerosis model, clopidogrel retards the progression of established lesions and that this effect is paralleled by a suppression of inflammatory factors.
Atherosclerosis 2007 Oct
PMID:Effect of clopidogrel on the inflammatory progression of early atherosclerosis in rabbits model. 1715 85

Angiotensin II is a potent vasoconstrictor and may also contribute to the progression of atherosclerosis. In atheromatous lesions located in human coronary and carotid arteries, angiotensin-converting enzyme and angiotensin II levels are significantly increased. Angiotensin II is known to have proinflammatory actions in vascular tissues, inducing inflammatory cytokines and oxidative stress. In particular, angiotensin II activates the potent cytoplasmic transcription factor nuclear factor-kappaB, which regulates leukocyte adhesion molecules, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-6, and contributes to the recruitment of circulating mononuclear leukocytes to the arterial intima. Olmesartan medoxomil has one of the highest degrees of antihypertensive efficacy among the angiotensin II type 1 receptor antagonists. In the EUTOPIA (EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis) trial, olmesartan medoxomil significantly reduced serum levels of high-sensitivity C-reactive protein, high-sensitivity TNFalpha, IL-6, and MCP-1, all of which are involved in promoting atherosclerosis. In a monkey atherosclerotic model, a 3-D intravascular ultrasound analysis of aortas showed that serum levels of MCP-1 and the degree of intimal hyperplasia were significantly lower after treatment with olmesartan medoxomil than before treatment. In VIOS (Vascular Improvement with Olmesartan Medoxomil Study), treatment with olmesartan medoxomil for 1 year, significantly reduced the wall-to-lumen ratio in arteries, whereas atenolol did not. Thus, olmesartan medoxomil, which rapidly reduces inflammatory markers, may have a beneficial antiatherosclerotic effect.
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PMID:Effect of olmesartan medoxomil on atherosclerosis: clinical implications of the emerging evidence. 1719 25


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