Simvastatin modulates TNFα-induced adhesion molecules expression in human endothelial cells

Zapolska-Downar, Danuta; Siennicka, Aldona; Kaczmarczyk, Mariusz; Kołodziej, Blanka; Naruszewicz, Marek

doi:10.1016/j.lfs.2004.03.005

Cited by 85 publications

(53 citation statements)

References 35 publications

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“…Statins are known to attenuate the recruitment of circulating leukocytes to endothelium including leukocytes rolling, adhesion, and transmigration [2,4,5,15,27], which represents a hallmark of vascular inflammation. Previous studies are limited to the impact of statins on ICAM-1, VCAM-1, E-selectin and P-selectin [2,16,17,27,28] which are inducible endothelial CAMs with functional relevance confined to leukocyte tethering and adhesion [29].…”

Section: Discussionmentioning

confidence: 99%

Statin‐inhibited endothelial permeability could be associated with its effect on PECAM‐1 in endothelial cells

Wei¹,

Lü²,

Song³

et al. 2005

FEBS Letters

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The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to inhibit leukocyte recruitment to endothelium but the mechanism is less understood. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an endothelial junction protein involved in leukocyte diapedesis. We hypothesize that in endothelial cells, statins may well recruit PECAM-1 to exert their inhibitory effect on leukocyte transendothelial migration (TEM). In lovastatin-treated resting human umbilical vein endothelial cells (HUVECs), increased levels of mRNA and protein of PECAM-1 as well as its bio-synthesis (all 2-fold) were observed by real-time PCR, Western blotting and 35 S-labeled methionine incorporation assay, respectively. Moreover, in lovastatin treated resting cells as well as TNF-a activated endothelial cells, unanimously decreased Triton X-100 insoluble and soluble PECAM-1 ratio was observed. Such changes were accompanied by decreased TEM of U-937 cells (a promonocyte cell line). All lovastatinÕs effects were abrogated by mevalonic acid. In resting HUVECs, geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP) (both are isoprenoid intermediates in the cholesterol biosynthesis pathway) compromised the effect of lovastatin on PECAM-1 expression, whereas C3 toxin, an inhibitor of small G proteins, exerted statin-like effect.Conclusion: Statin-reduced endothelial permeability could be attributed to altered intracellular distribution of PECAM-1 in endothelial cells. We speculate that lovastatin regulates PE-CAM-1 expression in HUVECs through the mevalonate-GGPP pathway by inhibiting of Rho small GTPase.

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Section: Discussionmentioning

confidence: 99%

Statin‐inhibited endothelial permeability could be associated with its effect on PECAM‐1 in endothelial cells

Wei¹,

Lü²,

Song³

et al. 2005

FEBS Letters

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“…Simvastatin inhibits in a time-and dose-dependent way the TNFa-induced upregulation of ICAM and VCAM-1 in HUVECs by reducing NF-jB activation; this leads to reduced monocyte-EC interactions (123). Importantly, in vitro exposure of human monocytes to pravastatin abrogates LDL-induced activation of NF-jB and subsequent expression of inflammatory mediators (124).…”

Section: Fig 7 Effects Of Statins On Nadph Oxidase In Ec Statins Smentioning

confidence: 98%

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

Margaritis

Channon

Antoniades

2014

Antioxidants & Redox Signaling

116

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Significance: Endothelial dysfunction and the imbalance between nitric oxide (NO) and reactive oxygen species production in the vascular endothelium are important early steps in atherogenesis, a major socioeconomic health problem. Statins have well-established roles in primary and secondary prevention of cardiovascular disease (CVD), due to both their lipid-lowering capacity and their pleiotropic properties. It is therefore important to understand the mechanisms by which statins can modify endothelial function and affect atherogenesis. Recent Advances: In the last decade, the concept of statin pleiotropy has been reinforced by a large number of cell culture, animal, and translational studies. Statins have been shown to suppress the activity of pro-oxidant enzymes (such as NADPH oxidase) and pro-inflammatory transcriptional pathways in the endothelium. At the same time, they enhance endothelial NO synthase expression and activity while they also improve its enzymatic coupling. This leads to increased NO bioavailability and improved endothelial function. Critical Issues: Despite significant recent advances, the exact mechanisms of statin pleitropy are still only partially understood. The vast majority of the published literature relies on animal studies, while the actual mechanistic studies in humans are limited. Future Directions: The success of statins as endothelium redox-modifying agents with a direct impact on clinical outcome highlights the importance of the endothelium as a therapeutic target in CVD. Better understanding of the mechanisms that underlie endothelial dysfunction could lead to the design of novel therapeutic strategies that target the vascular endothelium for the prevention and treatment of CVD. Antioxid. Redox Signal. 20, 1198Signal. 20, -1215

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“…Statins have been found to reduce the expression of VCAM-1 and ICAM-1 significantly in HUVECs (24). This is associated with reduced adherence of monocytes and lymphocytes (25). Furthermore, simvastatin prevents the growth and metastasis of squamous cell carcinoma in the head and neck through down-regulation of the β 1 integrin chain (26).…”

Section: Simvastatin Reduces Tumor Cell Adhesion To Human Peritoneal mentioning

confidence: 99%

Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin

et al. 2011

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Abstract. Peritoneal carcinomatosis describes cancer metastasis onto the surface of the peritoneum. It is frequently caused by ovarian and colorectal cancer. Once a tumor has penetrated the peritoneum, cancer cells disseminate into the abdominal cavity. Additionally, surgery can account for the spread of free tumor cells. Their subsequent adhesion to mesothelial cells (HMCs) initiates peritoneal carcinomatosis. Therefore, this study analyzed the effect of simvastatin on tumor cell adherence. HMCs were isolated from human greater omentum. Fluorescence-labeled tumor cells (SKOV-3, OvCar-29, OAW42, FraWü; ovarian/HT29; colorectal) were incubated on confluent mesothelial monolayers with 10 µM simvastatin for 48 h. Adhesion was quantified using a fluorescence reader. Expression of the adhesion molecules VCAM-1, ICAM-1 and β 1 integrin chain under the influence of simvastatin 0.1-100 µM for 24-72 h was analyzed using flow cytometry. Simvastatin significantly reduced the adhesion of all ovarian cancer cells and HT29 to HMCs (P≤0.001). Concomitantly simvastatin decreased the expression of VCAM-1 on HMCs. ICAM-1 and β 1 integrin chain expression on ovarian cancer cells was also clearly reduced. By contrast, the expression of the analyzed adhesion molecules on HT29 cells remained unchanged. Simvastatin clearly inhibits tumor cell adhesion to HMCs. In the case of ovarian cancer cell lines it appears to be mediated by decreased expression of both VCAM-1 on HMCs and the integrin α 4 β 1 on tumor cells. As an example of adhesion molecule down-regulating drugs, simvastatin may provide a novel therapeutic approach to the prevention of peritoneal carcinomatosis.

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Simvastatin modulates TNFα-induced adhesion molecules expression in human endothelial cells

Cited by 85 publications

References 35 publications

Statin‐inhibited endothelial permeability could be associated with its effect on PECAM‐1 in endothelial cells

Statin‐inhibited endothelial permeability could be associated with its effect on PECAM‐1 in endothelial cells

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin

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