Inhibition of mammalian target of rapamycin modulates expression of adhesion molecules in endothelial cells

Wood, Steven C.; Bushar, Grace; Tesfamariam, Belay

doi:10.1016/j.toxlet.2006.04.009

Cited by 14 publications

(10 citation statements)

References 32 publications

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“…Previous reports strengthen our data and showed that the TNF-induced expression of VCAM-1 was not affected by Eve [37]. In contrast, Sir downregulated complement-induced ICAM-1 expression in a concentration-dependent manner on immortalized porcine aortic EC [38]. This may be due to different stimulation mechanisms comparing TNF and complement, and the fact that our cells were not serum starved.…”

Section: Discussionsupporting

confidence: 85%

mTOR Inhibitors and Calcineurin Inhibitors Do Not Affect Adhesion Molecule Expression of Human Macro- and Microvascular Endothelial Cells

Lehle

Schreml²,

Kunz-Schughart³

et al. 2008

J Vasc Res

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We examined the effect of cyclosporin A, tacrolimus, sirolimus and everolimus on the cell growth, viability, proliferation, expression of cellular adhesion molecules (CAM) and leukocyte (PBMC) binding of human macrovascular (coronary artery, saphenous vein) and microvascular endothelial cells (EC). Tacrolimus did not affect EC integrity, growth or expression of CAM. Exclusively, EC from the coronary arteries showed a reduced cellular growth (about 30%) under cyclosporin A and tacrolimus treatment. In contrast, treatment with mTOR inhibitors reduced EC proliferative activity by about 40%, independently of the EC origin. No induction of apoptosis (caspase-3/7 activity) or cytotoxicity (MTS test) was observed. Long-term treatment with high concentrations of sirolimus and everolimus did not enhance the expression of CAM. Stimulation with tumor necrosis factor significantly increased the expression of CAM, independently of the drugs used. None of the mTOR inhibitors influenced the tumor necrosis factor-induced expression of CAM, whereas adhesion of PBMC increased significantly, as described by other papers. In summary, neither calcineurin inhibitors nor mTOR inhibitors activate human micro- and macrovascular EC. Therefore, the investigated drugs are unlikely to contribute to EC activation during transplant-associated vasculopathy.

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Section: Discussionsupporting

confidence: 85%

mTOR Inhibitors and Calcineurin Inhibitors Do Not Affect Adhesion Molecule Expression of Human Macro- and Microvascular Endothelial Cells

Lehle

Schreml²,

Kunz-Schughart³

et al. 2008

J Vasc Res

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show abstract

“…In summary, our results link the nutrient-responsive Tor signal transduction cascade to regulation of cell–cell adhesion in a major human fungal pathogen. Rapamycin also modulates aggregation of C. guilliermondii cells (Figure S1), and expression of adhesion molecules in mammalian endothelial cells [55], opening the possibility that Tor1's regulation of cell–cell adhesion might be broadly conserved among organisms including metazoans.…”

Section: Discussionmentioning

confidence: 99%

The Protein Kinase Tor1 Regulates Adhesin Gene Expression in Candida albicans

2009

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Eukaryotic cell growth is coordinated in response to nutrient availability, growth factors, and environmental stimuli, enabling cell–cell interactions that promote survival. The rapamycin-sensitive Tor1 protein kinase, which is conserved from yeasts to humans, participates in a signaling pathway central to cellular nutrient responses. To gain insight into Tor-mediated processes in human fungal pathogens, we have characterized Tor signaling in Candida albicans. Global transcriptional profiling revealed evolutionarily conserved roles for Tor1 in regulating the expression of genes involved in nitrogen starvation responses and ribosome biogenesis. Interestingly, we found that in C. albicans Tor1 plays a novel role in regulating the expression of several cell wall and hyphal specific genes, including adhesins and their transcriptional repressors Nrg1 and Tup1. In accord with this transcriptional profile, rapamycin induced extensive cellular aggregation in an adhesin-dependent fashion. Moreover, adhesin gene induction and cellular aggregation of rapamycin-treated cells were strongly dependent on the transactivators Bcr1 and Efg1. These findings support models in which Tor1 negatively controls cellular adhesion by governing the activities of Bcr1 and Efg1. Taken together, these results provide evidence that Tor1-mediated cellular adhesion might be broadly conserved among eukaryotic organisms.

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“…Neointimal hyperplasia is accelerated by the influx of inflammatory cells, and increased cell adhesion molecules, and the proliferation of the smooth muscle cells could be overcome by agents which inhibit the phases of the cell cycle. 4 The elution of drugs, such as paclitaxel, from a polymer carrier matrix of stent systems has been shown to be effective in the prevention of neointimal hyperplasia, and thus reduces restenosis. The stent-based drug delivery system is very efficient, and that high concentrations of drugs can accumulate in the local vascular tissues.…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel Potentiates Inflammatory Cytokine-induced Prothrombotic Molecules in Endothelial Cells

Wood¹,

Xing²,

Tesfamariam³

2010

Journal of Cardiovascular Pharmacology

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To overcome the limitations of balloon expandible metal stent-induced neointimal smooth muscle cell proliferation, drug-coated stent devices have been developed. Drug eluting stents release high concentrations of antiproliferative agents, such as paclitaxel, to reduce neointimal hyperplasia. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), is known to cause severe endothelial dysfunction and accelerate atherosclerotic lesion progression. The interaction of TNF-alpha and paclitaxel on the release of prothrombotic molecules was examined in endothelial cells. Treatment of endothelial cells with paclitaxel had no direct effect on tissue factor (TF) expression, but TNF-alpha increased TF. Cotreatment of paclitaxel with TNF-alpha markedly augmented the release of TF. TNF-alpha induced release of plasminogen activator inhibitor but no synergism occurred with paclitaxel. Treatment of endothelial cells with paclitaxel and TNF-alpha reduced expression of thrombomodulin and protein C receptor. Tissue factor pathway inhibitor expression was reduced by prolonged treatment with either paclitaxel or TNF-alpha. The adhesion molecule, CD62 E, was induced by TNF-alpha; however, CD31, CD62 P, and CD106 were not affected by paclitaxel and TNF-alpha. Apoptosis was not observed with cotreatment of endothelial cells with paclitaxel and TNF-alpha. CD59-positive microparticles were released in response to TNF-alpha, but the release was not augmented by paclitaxel. Paclitaxel and TNF-alpha increased the nitrotyrosination of proteins. These findings indicate that paclitaxel enhances TNF-alpha-induced release of TF, and downregulated thrombomodulin, increased protein nitration, which may subsequently favor prothrombotic intimal surface.

show abstract

Inhibition of mammalian target of rapamycin modulates expression of adhesion molecules in endothelial cells

Cited by 14 publications

References 32 publications

mTOR Inhibitors and Calcineurin Inhibitors Do Not Affect Adhesion Molecule Expression of Human Macro- and Microvascular Endothelial Cells

mTOR Inhibitors and Calcineurin Inhibitors Do Not Affect Adhesion Molecule Expression of Human Macro- and Microvascular Endothelial Cells

The Protein Kinase Tor1 Regulates Adhesin Gene Expression in Candida albicans

Paclitaxel Potentiates Inflammatory Cytokine-induced Prothrombotic Molecules in Endothelial Cells

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