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)

Long-term exposure to particulate air pollution has been implicated as a risk factor for cardiovascular disease and mortality. Short-term exposure has also been suggested to contribute to complications of atherosclerosis. Aberrant regulation of smooth muscle cell proliferation is thought to associate with the pathophysiology of vascular disorders such as atherosclerosis. In this study, we investigate the influence of organic extracts of motorcycle exhaust particulates (MEPE) on rat vascular smooth muscle cell (VSMC) proliferation and related regulation signaling. Exposure of VSMCs to MEPE (10-100 microg/mL) enhanced serum-induced VSMC proliferation. The expression of proliferating cell nuclear antigen (PCNA) was also enhanced in the presence of MEPE. VSMCs treated with MEPE induced the increase in the extent of cyclooxygenase (COX)-2 mRNA and protein expression and prostaglandin E 2 production, whereas the level of COX-1 protein was unchanged. Moreover, MEPE increased the production of reactive oxygen species (ROS) in VSMCs in a dose-dependent manner. MEPE could also trigger time-dependently extracellular signal-regulated kinase (ERK)1/2 phosphorylation in VSMCs, which was attenuated by antioxidants N-acetylcysteine (NAC) and pyrrolidinedithiocarbamate (PDTC). The level of translocation of nuclear factor (NF)-kappaB-p65 in the nuclei of VSMCs was also increased under MEPE exposure. The potentiating effect of MEPE on serum-induced VSMC proliferation could be abolished by COX-2 selective inhibitor NS-398, specific ERK inhibitor PD98059, and antioxidants NAC and PDTC. Taken together, these findings suggest that MEPE may contribute to the enhancement of the pathogenesis of cardiovascular diseases by augmenting proliferation of VSMCs through a ROS-regulated ERK1/2-activated COX-2 signaling pathway.
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PMID:Upregulation of cyclooxygenase-2 by motorcycle exhaust particulate-induced reactive oxygen species enhances rat vascular smooth muscle cell proliferation. 1764 4

TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) is a multifunctional protein regulating homeostasis of the immune system, infection, autoimmune diseases, and apoptosis. However, its function in normal, nontransformed tissues is not clear. Here we show that TRAIL increases vascular smooth muscle cell (VSMC) proliferation in vitro, effects that can be blocked with neutralizing antibodies to TRAIL receptors DR4 and DcR1. In aortocoronary saphenous vein bypass grafts in vivo, TRAIL co-localizes with VSMC, proliferating cell nuclear antigen, and insulin-like growth factor type 1 receptor (IGF1R) expression but not active caspase-3. TRAIL is required for serum-inducible IGF1R expression, and antisense IGF1R inhibits TRAIL-induced VSMC proliferation. At 1 ng/ml, TRAIL stimulates IGF1R mRNA expression greater than insulin-like growth factor-1 and also activates the IGF1R promoter 7-fold. TRAIL-inducible IGF1R expression requires NF-kappaB activation. Consistent with this, ammonium pyrrolidine dithiocarbamate, a pharmacological inhibitor of NF-kappaB, blocks TRAIL-induced IGF1R expression, and p65 overexpression increases IGF1R protein levels. In addition, NF-kappaB binds a novel TRAIL-responsive element on the IGF1R promoter. Our findings suggest that the biological functions of TRAIL in VSMC extend beyond its role in promoting apoptosis. Thus, TRAIL may play an important role in atherosclerosis by regulating IGF1R expression in VSMC in an NF-kappaB-dependent manner.
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PMID:TRAIL stimulates proliferation of vascular smooth muscle cells via activation of NF-kappaB and induction of insulin-like growth factor-1 receptor. 1817 61

Proliferation of intimal vascular smooth muscle cells is an important component in the development of atherosclerosis. Ellagic acid is a phenolic compound present in fruits (raspberries, blueberries, strawberries) and walnuts. The present study investigated the effect of ellagic acid on the oxidised LDL (ox-LDL)-induced proliferation of rat aortic smooth muscle cells (RASMC). The study found that ellagic acid significantly inhibited ox-LDL-induced proliferation of RASMC and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Furthermore, ellagic acid also blocked the ox-LDL-induced (inducible) cell-cycle progression and down regulation of the expression of proliferating cell nuclear antigen (PCNA) in RASMC. Therefore, ellagic acid reduced the amount of ox-LDL-induced proliferation of RASMC via inactivation of the ERK pathway and suppression of PCNA expression. These results may significantly advance the understanding of the role that antioxidants play in the prevention of atherosclerosis.
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PMID:Ellagic acid suppresses oxidised low-density lipoprotein-induced aortic smooth muscle cell proliferation: studies on the activation of extracellular signal-regulated kinase 1/2 and proliferating cell nuclear antigen expression. 1818 51

To evaluate the possible role of ghrelin in the development of atherosclerosis, its effects on tumor necrosis factor (TNF)-alpha-induced proliferation and apoptosis of vascular smooth muscle cells (VSMCs) were investigated. Rat VSMCs were pretreated with different concentrations of ghrelin and then with TNF-alpha. VSMC proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and flow cytometry method. Apoptosis was detected using propidium iodide and Annexin-V labeling method. Exogenous ghrelin (10-1000 ng/ml) significantly inhibited TNF-alpha-induced proliferation of VSMCs in a concentration-dependent manner. Treatment with 1000 ng/ml ghrelin was most effective at inhibiting VSMC proliferation rate and the expression of proliferating cell nuclear antigen. However, treatment with des-acyl ghrelin affected neither proliferation nor PCNA expression. In contrast, TNF-alpha-induced apoptosis of VSMCs was inhibited by both ghrelin and des-acyl ghrelin in concentration-dependent manners, with maximal inhibition observed for both compounds at 1000 ng/ml. Taken together, our results suggested that ghrelin inhibited both the proliferation and apoptosis of rat VSMCs. Furthermore, the former effect is probably mediated by the growth hormone secretagogue receptor type 1a receptor, while the latter effect may be mediated through other receptors.
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PMID:Inhibition of proliferation and apoptosis of vascular smooth muscle cells by ghrelin. 1877 88

Vascular remodeling is influenced by trauma and proatherogenic factors such as cholesterol. It has been shown that cholesterol exerts a direct effect on vessel wall structure. In this study we evaluated the effects of vascular trauma and cholesterol treatment on vascular remodeling and plaque integrity in carotid ligated ApoE-deficient mice. The right carotid artery was ligated in mice fed regular chow or cholesterol and fat containing diet. After 4 weeks left (non-ligated) and right (ligated) carotids were prepared. For studying vascular remodeling the vascular areas were evaluated morphometrically by calculating the areas from circumference measurements on Verhoff-van Gieson stains. The cellular and structural features of the plaque were analyzed by histological staining and immunohistochemistry. Under regular chow total vessel area decreased by 35% (p<0.001); cholesterol-rich diet led to an increase by 20% (p<0.05). In both feeding groups ligated carotids presented neointima development. The medial area increased only in mice fed regular chow. The luminal area was reduced by 80% (regular chow: p<0.001) and by 90% (cholesterol-rich diet: p<0.01). Regular chow led to structured plaques showing the typical features of stable plaques. Under cholesterol diet well defined plaque structures were missing. These lesions were characterized by numerous macrophages, few mostly PCNA positive smooth muscle cell (SMC) and less collagen particularly in the shoulder region. Our data indicate that in ApoE-deficient mice both direction of the remodeling response and lesion integrity are due to the diet applied: regular chow led to constrictive remodeling, whereas cholesterol and fat containing diet was associated with an adaptive response. Our data further indicate that the direction of response is not only related to the macrophage content but also to a proliferative intimal SMC-phenotype. Our data implicate that high serum cholesterol levels are not only inducers of plaque instability but also of the so far "positively recorded" compensatory remodeling.
Atherosclerosis 2009 May
PMID:Vascular remodeling in ApoE-deficient mice: diet dependent modulation after carotid ligation. 1884 22

Oxidized low density lipoprotein (oxLDL) plays an important role in the development of atherosclerosis partly through an action on cell proliferation and cell apoptosis. Nuclear protein import (NPI) is critical in regulating gene expression, transcription, and subsequently cell proliferation and apoptosis. The aim of this study was to determine if exposure of vascular smooth muscle cells (VSMC) to oxLDL affects cell growth by inducing alterations in NPI and nuclear pore density. VSMC were exposed for different times to oxLDL. Cells were then injected with a protein import substrate (Alexa488-BSA-NLS) to visually monitor nuclear transport with the confocal microscope. The effect of MAPK inhibitors (SB203580 and PD98059) was investigated and western immunoblottings were also performed. Shorter exposure times of VSMC to oxLDL, but not to native LDL, significantly increased NPI, nuclear pore expression (p62), PCNA expression, and cell number. These changes occurred through an ERK MAPK-dependent mechanism. However, longer exposures to oxLDL decreased NPI, nuclear pore expression, and increased apoptosis marker (cleaved PARP) expression through a p38 MAPK-dependent mechanism. We conclude that limited exposure to oxLDL may influence cell proliferation and apoptosis through an action on nucleocytoplasmic trafficking. The nucleus and NPI may represent a novel therapeutic target to control diseases like atherosclerosis that have changes in cell growth as a central feature.
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PMID:Oxidized LDL affects smooth muscle cell growth through MAPK-mediated actions on nuclear protein import. 1901 Mar 32

Neointima formation participates in the pathophysiology of atherosclerosis and restenosis. Proliferation and migration of vascular smooth muscle cells (VSMC) are initial responses to vascular injury. The aim of the present study was to assess the effect of gliotoxin, an inhibitor of nuclear factor (NF)-kappaB, on migration and proliferation of cultured rat VSMC and neointimal formation in injured rat vessels. In cultured VSMC, gliotoxin inhibited the nuclear translocation of the p65 subunit of NF-kappaB in response to inflammatory stimuli. In addition, gliotoxin inhibited VSMC migration and proliferation in response to platelet-derived growth factor-BB. This was associated with a rapid rearrangement of the F-actin and vimentin cytoskeleton. Furthermore, gliotoxin inhibited endothelial cell nuclear translocation of p65, cell surface expression of adhesion molecules such as VCAM-1, ICAM-1 and E-selectin, and monocytic cell adhesion to a cytokine-activated endothelial monolayer. In the rat carotid artery balloon catheter injury model, the systemic administration of gliotoxin for 10 days decreased neointimal hyperplasia and luminal stenosis by up to 90% and decreased the expression of proliferating cell nuclear antigen in the vessel wall by up to 70%, depending on the dose. These observations suggest that gliotoxin favorably regulates the response to vascular injury through actions on VSMC. However, further studies evaluating the therapeutic benefit of gliotoxin in restenosis after balloon angioplasty are required.
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PMID:Gliotoxin inhibits neointimal hyperplasia after vascular injury in rats. 1903 90

Recent epidemiologic studies have suggested that serum dehydroepiandrosterone sulfate (DHEAS) levels have a significant inverse correlation with the incidence of cardiovascular diseases. However, direct evidence for the association with DHEAS and vascular disorders has not yet been explored. DHEAS significantly reduced neointima formation 28 days after surgery without altering other serum metabolite levels in a rabbit carotid balloon injury model. Immunohistochemical analyses revealed the reduction of proliferating cell nuclear antigen (PCNA) index and increase of TdT-mediated dUTP-biotin Nick End Labeling (TUNEL) index, expressing differentiated vascular smooth muscle cell (VSMC) markers in the media 7 days after surgery. In vitro, DHEAS exhibited inhibitory effects on VSMC proliferation and migration activities, inducing G1 cell cycle arrest with upregulation of one of the cyclin dependent kinase (CDK) inhibitors p16(INK4a) and apoptosis with activating peroxisome proliferator-activated receptor (PPAR)-alpha in VSMCs. DHEAS inhibits vascular remodeling reducing neointima formation after vascular injury via its effects on VSMC phenotypic modulation, functions and apoptosis upregulating p16(INK4a)/activating PPARalpha. DHEAS may play a pathophysiological role for vascular remodeling in cardiovascular disease.
Atherosclerosis 2009 Sep
PMID:Adrenal androgen dehydroepiandrosterone sulfate inhibits vascular remodeling following arterial injury. 1929 64

Recently, the herbal extract of Hibiscus sabdariffa was shown to have multiple bioactive effects, including anti-atherosclerosis. On the basis of this, we aimed to examine whether the polyphenolic isolate of H. sabdariffa (HPI) could protect high-glucose-treated vascular smooth muscle cell (VSMC) and its putative transduction signals. Results showed that HPI dose- and time-dependently reduced the high-glucose-stimulated cell proliferation and migration. HPI suppressed the proliferating cell nuclear antigen (PCNA) level and matrix metalloproteinase (MMP)-2 activation. In addition, the expressions of connective tissue growth factor (CTGF) and receptor of advanced glycation end product (RAGE) enhanced by high glucose were prominently suppressed by HPI. The proliferation signal mediated by high glucose was demonstrated via CTGF/RAGE, while MMP-2 was regulated by CTGF but not RAGE. Conclusively, the results suggest that HPI potentially can be a promising adjuvant herbal therapy for diabetic patients.
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PMID:Hibiscus sabdariffa inhibits vascular smooth muscle cell proliferation and migration induced by high glucose--a mechanism involves connective tissue growth factor signals. 1930 17

Although cellular proliferation is a key component in the progression of atherosclerosis, research so far has been focused primarily on VSMCs. In this study we attempted to evaluate overall proliferation rates in general, as well as foam cells and the endothelial cells lining newly formed plaque microvessels in particular. For this purpose, cellular proliferation was assessed through immunohistochemical staining for PCNA in 10 fresh human carotid artery samples received from patients undergoing carotid endarterectomy. Overall proliferative activity was found significantly higher (P<or=0.01) among complicated type VI lesions compared to uncomplicated type V lesions. A similar assessment focused on foam cells alone also revealed a significantly higher (P<or=0.05) proliferative index among complicated lesions. On the other hand, the proliferation rate for the endothelial cells lining the interior walls of newly formed microvessels was harder to properly assess, since only two of the uncomplicated lesions bore signs of neovascularization. Still, both of these samples displayed proliferation rates similar to those of the complicated type VI lesions. Thus, it seems that, although total cell population and foam cells are probably affected by the stimulating factors that are expressed during acute events, the same does not apply to the endothelial cells lining plaque vessels.
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PMID:Cellular proliferation in complicated versus uncomplicated atherosclerotic lesions: total cell population, foam cells and newly formed microvessels. 1963 56


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