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)

Constitutive activation of serine/threonine kinase Akt causes uncontrolled cell-cycle progression in different cell types and in malignancy. To investigate how Akt activation modulates cell-cycle progression in vascular smooth muscle cells (SMCs) in vitro and in the intact animal, we inhibited Akt-dependent signaling by adenovirus-mediated transfection of a dominant-negative Akt mutant (AA-Akt). We observed reduced proliferation rate (P<0.01), DNA synthesis (P<0.01), and a significant arrest in G1/S exit (P<0.01) both in vitro in response to serum stimulation and in vivo after vascular injury. In vivo transfection of the balloon-injured vessel with AA-Akt reduced SMC proliferation, resulting in decreased neointima compared with control virus (P<0.01). These effects were at least in part modulated, both in vitro and in vivo, by increased p21Cip1 expression, as demonstrated by lack of effect of AA-Akt on cell proliferation in p21-/- mouse SMCs. In conclusion, this study demonstrates that Akt-dependent signaling enhances cell-cycle progression of nontransformed SMCs in vitro and in response to vascular injury in the intact animal. These results suggest a role for Akt signaling in modulating the response of normal tissues to stress and the response of the arterial wall to acute and possibly repetitive injuries that ultimately contribute to restenosis and atherosclerosis.
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PMID:Akt controls vascular smooth muscle cell proliferation in vitro and in vivo by delaying G1/S exit. 1460 18

Increased aortic smooth muscle cell (SMC) proliferation is a key event in the pathogenesis of atherosclerosis. Transforming growth factor-beta (TGF-beta) is one of the potent inhibitors of SMC proliferation. The purpose of this study was 1) to explore the effect of TGF-beta inhibition on proliferation of SMC and expression of growth regulatory molecules like p21 and c-myc and 2) to determine whether restoration of cell cycle regulatory molecules normalizes the altered proliferation. To test the role of TGF-beta in SMC proliferation, using antisense plasmid DNA, we inhibited TGF-beta gene from aortic SMC, which resulted in a significant increase (P < 0.03) in proliferation (studied by quantifying new DNA synthesis with [(3)H]thymidine uptake assay). In TGF-beta-altered SMC (TASMC), the mRNA expression (studied by RT-PCR) of c-myc was increased whereas that of the cyclin inhibitor p21 was completely inhibited. Using p21 sense plasmid DNA, we transfected p21 gene in TASMC, which restored p21 mRNA and protein expression and decreased proliferation (P < 0.002) in TASMC. Similar treatment with c-myc antisense oligonucleotides significantly (P < 0.001) decreased the proliferation of TASMC. TASMC also exhibited alteration in morphological changes in SMC but returned to normal with treatment of p21 and TGF-beta sense plasmid DNA. Two-dimensional gel electrophoresis analysis of SMC and TASMC demonstrated differential expression of proteins relevant to cellular proliferation and atherosclerosis. This study uniquely analyzes the effect of TGF-beta at the molecular level on proliferation of SMC and on cell cycle regulatory molecules, implicating their potential role in the pathogenesis of atherosclerosis.
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PMID:Concerted effect of transforming growth factor-beta, cyclin inhibitor p21, and c-myc on smooth muscle cell proliferation. 1476 78

Reduction-of-function mutations in components of the insulin/insulin-like growth factor-1/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. It has also been reported that activation of Akt induces proliferation and survival of mammalian cells, thereby promoting tumorigenesis. We have recently shown that Akt activity increases with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human diseases including atherosclerosis and diabetes mellitus.
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PMID:Akt-induced cellular senescence: implication for human disease. 1500 30

In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury.
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PMID:Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease. 1503 Dec 6

Inflammation-responsive transcription factor, serum amyloid A-activating factor 1 (SAF-1), has been shown to regulate several genes, including serum amyloid A, gamma-fibrinogen, and matrix metalloproteinase 1, whose abnormal expression is associated with the pathogenesis of arthritis, atherosclerosis, and amyloidosis. Prolonged high level expression of SAF-1 in cultured cells failed to produce any stable cell line that overexpresses SAF-1. To test the fate of SAF-1-overexpressing cells, the cells were monitored for growth and morphological changes over time. The cells that were programmed to overproduce SAF-1 were found to undergo growth arrest and reduce DNA synthesis within 3 days after transfection. These cells undergo marked morphological changes from typical fibroblasts to round morphology and gradually cease to exist. Microarray analysis for cell cycle-specific genes in SAF1-transfected cells identified several candidate genes whose expression levels were altered during SAF-1 overexpression. Cdk inhibitor protein p21 was significantly affected by SAF-1; its expression level was highly induced by cellular conditions where SAF-1 is abundant. The increased level of p21 in the cell drives it to a growth arrest mode, a condition previously found to be controlled by p53. In this study we provide evidence that, similar to p53, SAF-1 is able to activate p21 gene expression by promoting transcription directly via its interaction with the p21 promoter. Together these data indicate that SAF-1 controls cell cycle progression via p21 induction, and pathophysiological conditions that favor overexpression of SAF-1, such as an acute inflammatory condition, can trigger cellular growth arrest.
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PMID:Overexpression of serum amyloid A-activating factor 1 inhibits cell proliferation by the induction of cyclin-dependent protein kinase inhibitor p21WAF-1/Cip-1/Sdi-1 expression. 1506 82

Sialic acid-containing glycosphingolipids (gangliosides) have been implicated in the regulation of various biological phenomena such as atherosclerosis. Recent report suggests that exogenously supplied disialoganglioside (GD3) serves a dual role in vascular smooth muscle cells (VSMC) proliferation and apoptosis. However, the role of the GD3 synthase gene in VSMC responses has not yet been elucidated. To determine whether a ganglioside is able to modulate VSMC growth, the effect of overexpression of the GD3 synthase gene on DNA synthesis was examined. The results show that the overexpression of this gene has a potent inhibitory effect on DNA synthesis and ERK phosphorylation in cultured VSMC in the presence of PDGF. The suppression of the GD3 synthase gene was correlated with the down-regulation of cyclinE/CDK2, the up-regulation of the CDK inhibitor p21 and blocking of the p27 inhibition, whereas up-regulation of p53 as the result of GD3 synthase gene expression was not observed. Consistently, blockade of GD3 function with anti-GD3 antibody reversed VSMC proliferation and cell cycle proteins. The expression of the GD3 synthase gene also led to the inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by zymography and immunoblot. Furthermore, GD3 synthase gene expression strongly decreased MMP-9 promoter activity in response to TNF-alpha. This inhibition was characterized by the down-regulation of MMP-9, which was transcriptionally regulated at NF-kappaB and activation protein-1 (AP-1) sites in the MMP-9 promoter. Finally, the overexpression of MMP-9 in GD3 synthase transfectant cells rescued VSMC proliferation. However, MMP-2 overexpression was not affected by cell proliferation. These findings suggest that the GD3 synthase gene represents a physiological modulator of VSMC responses that may contribute to plaque instability in atherosclerosis.
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PMID:Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle progression, and matrix metalloproteinase-9 expression. 1517 38

The regulation of vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis plays a clear role in the atherosclerotic process. Recently, we reported on the inhibition of the exaggerated growth phenotype of VSMCs isolated from hypertensive rats by lipocalin-type prostaglandin D2 synthase (L-PGDS). In the present study, we report the differential effects of L-PGDS on VSMC cell cycle progression, migration, and apoptosis in wild-type VSMCs vs. those from a type 2 diabetic model. In wild-type VSMCs, exogenously added L-PGDS delayed serum-induced cell cycle progression from the G1 to S phase, as determined by gene array analysis and the decreased protein expressions of cyclin-dependent kinase-2, p21(Cip1), and cyclin D1. Cyclin D3 protein expression was unaffected by L-PGDS, although its gene expression was stimulated by L-PGDS in wild-type cells. In addition, platelet-derived growth factor-induced VSMC migration was inhibited by L-PGDS in wild-type cells. Type 2 diabetic VSMCs, however, were resistant to the L-PGDS effects on cell cycle progression and migration. L-PGDS did suppress the hyperproliferation of diabetic cells, albeit through a different mechanism, presumably involving the 2.5-fold increase in apoptosis and the concomitant 10-fold increase of L-PGDS uptake we observed in these cells. We propose that in wild-type VSMCs, L-PGDS retards cell cycle progression and migration, precluding hyperplasia of the tunica media, and that diabetic cells appear resistant to the inhibitory effects of L-PGDS, which consequently may help explain the increased atherosclerosis observed in diabetes.
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PMID:Inhibition of cell cycle progression and migration of vascular smooth muscle cells by prostaglandin D2 synthase: resistance in diabetic Goto-Kakizaki rats. 1524 Mar 44

Vascular proliferative disorders, such as atherosclerosis and restenosis, are the most common causes of severe cardiovascular diseases, but a common molecular mechanism remains elusive. Here, we identify and characterize a novel hyperplasia suppressor gene, named HSG (later re-named rat mitofusin-2). HSG expression was markedly reduced in hyper-proliferative vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rat arteries, balloon-injured Wistar Kyoto rat arteries, or ApoE-knockout mouse atherosclerotic arteries. Overexpression of HSG overtly suppressed serum-evoked VSMC proliferation in culture, and blocked balloon injury induced neointimal VSMC proliferation and restenosis in rat carotid arteries. The HSG anti-proliferative effect was mediated by inhibition of ERK/MAPK signalling and subsequent cell-cycle arrest. Deletion of the p21(ras) signature motif, but not the mitochondrial targeting domain, abolished HSG-induced growth arrest, indicating that rHSG-induced anti-proliferation was independent of mitochondrial fusion. Thus, rHSG functions as a cell proliferation suppressor, whereas dysregulation of rHSG results in proliferative disorders.
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PMID:Dysregulation of HSG triggers vascular proliferative disorders. 1534 Apr 47

Smooth muscle cells (SMC) play a central role in common vascular pathologies such as atherosclerosis and restenosis. Understanding the molecular regulation of SMC proliferation at a transcriptional level may provide important clues for the targeted control of vascular hyperplasia. We recently reported the capacity of the transcription factor Sp1 to down-regulate p21(WAF1/Cip1) production thereby reducing p21(WAF1/Cip1)-cyclin D1-Cdk4 complex formation and inhibiting vascular SMC proliferation (Kavurma and Khachigian [2003] J. Biol. Chem. 278, 32537-32543). We have now localized the Sp1-response elements in the p21(WAF1/Cip1) promoter responsible for p21(WAF1/Cip1) repression in WKY12-22 SMCs. The proximal region of the p21(WAF1/Cip1) promoter contains five distinct Sp1-binding elements that we have termed A, B, C, D, and E. Electrophoretic mobility shift analysis revealed that SMC nuclear Sp1 interacts with all five Sp1-binding sites, and each of these sites is critical for Sp1 repression of the p21(WAF1/Cip1) promoter, since mutation in any one element ablates repression, and in some cases results in activation. In contrast, only elements C, D, and E are bound by Sp1 in endothelial cells. Sp1 overexpression activates the p21(WAF1/Cip1) promoter in this cell type. Furthermore, mutation in any of these five elements is not sufficient to prevent activation of the p21(WAF1/Cip1) promoter by Sp1 in endothelial cells. Surprisingly, double mutations of elements C and E facilitates superactivation by Sp1 in both cell types, whereas triple mutations of C, D, and E inactivate the promoter. These findings demonstrate cell type-specific regulation of p21(WAF1/Cip1) transcription by Sp1 via distinct cis-acting positive and negative regulatory elements in the proximal p21(WAF1/Cip1) promoter.
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PMID:Vascular smooth muscle cell-specific regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1) transcription by Sp1 is mediated via distinct cis-acting positive and negative regulatory elements in the proximal p21(WAF1/Cip1) promoter. 1538 73

It has been suggested that epigallocatechin-3-gallate (EGCG), a major catechin found in green tea, plays a role in preventing the progression of atherosclerosis. Although EGCG has anti-atherogenic effects on vascular smooth muscle cells (VSMC), the molecular mechanisms associated with TNF-alpha-induced VSMC are not known with certainty. To determine whether EGCG has the capacity to modulate VSMC responses, cell cycle regulation and MMP-9 expression were examined in TNF-alpha-induced VSMC. Treatment with EGCG, which blocks the cell cycle in the G(1) phase, induced a down-regulation of cyclins and CDKs and an up-regulation in the expression of p21/WAF1, a CDK inhibitor, whereas the up-regulation of p27 by EGCG was not observed. Moreover, treatment with EGCG markedly increased the promoter activity of the p21/WAF1 gene. Immunoblot and deletion analysis results for the p21/WAF1 promoter showed that EGCG induced the expression of p21/WAF1 independent of the p53 pathway. Zymographic and immunoblot analyses showed that EGCG suppressed TNF-alpha-induced MMP-9 expression in a dose-dependent manner. Further experiments demonstrated that EGCG reduced the transcriptional activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), two important nuclear transcription factors that are involved in MMP-9 expression. Collectively, these results suggest that EGCG inhibits G(1) to S-phase cell cycle progress and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC.
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PMID:Epigallocatechin-3-gallate causes the p21/WAF1-mediated G(1)-phase arrest of cell cycle and inhibits matrix metalloproteinase-9 expression in TNF-alpha-induced vascular smooth muscle cells. 1570 69


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