Neutral sphingomyelinase inhibitor scyphostatin prevents and ceramide mimics mechanotransduction in vascular endothelium

Czarny, Malgorzata; Schnitzer, Jan E.

doi:10.1152/ajpheart.00222.2004

Cited by 63 publications

(55 citation statements)

References 49 publications

(65 reference statements)

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“…34 It has also been reported that sphingomyelin hydrolysis is activated on shear stress. 35 To examine the effect of shear stress on S1P synthesis and release by endothelial cells, we subjected MEECs to laminar shear stress. The p42/p44 extracellular signal-regulated kinase was rapidly phosphorylated when the endothelial cells were subjected to laminar shear stress (supplemental Figure IV).…”

Section: Shear Stress Induces S1p Release By Endothelial Cellsmentioning

confidence: 99%

Vascular Endothelium As a Contributor of Plasma Sphingosine 1-Phosphate

Venkataraman

Lee

Michaud

et al. 2008

Circulation Research

429

421

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Abstract-Sphingosine 1-phosphate (S1P), an abundant lipid mediator in plasma, regulates vascular and immune cells by activating S1P receptors. In this report, we investigated the mechanisms by which high plasma S1P levels are maintained in mice. We found that plasma S1P turns over rapidly with a half-life of Ϸ15 minutes, suggesting the existence of a high-capacity biosynthetic source(s). Transplantation of bone marrow from wild-type to Sphk1 Ϫ/Ϫ Sphk2 ϩ/Ϫ mice restored plasma S1P levels, suggesting that hematopoietic cells are capable of secreting S1P into plasma. However, plasma S1P levels were not appreciably altered in mice that were thrombocytopenic, anemic, or leukopenic. Surprisingly, reconstitution of Sphk1 Ϫ/Ϫ Sphk2 ϩ/Ϫ bone marrow cells into wild-type hosts failed to reduce plasma S1P, suggesting the existence of an additional, nonhematopoietic source for plasma S1P. Adenoviral expression of Sphk1 in the liver of Sphk1 Ϫ/Ϫ mice restored plasma S1P levels. In vitro, vascular endothelial cells, but not hepatocytes, secreted S1P in a constitutive manner. Interestingly, laminar shear stress downregulated the expression of S1P lyase (Sgpl) and S1P phosphatase-1 (Sgpp1) while concomitantly stimulating S1P release from endothelial cells in vitro. Modulation of expression of endothelial S1P lyase with small interfering RNA and adenoviral expression altered S1P secretion, suggesting an important role played by this enzyme. These data suggest that the vascular endothelium, in addition to the hematopoietic system, is a major contributor of plasma S1P. Key Words: sphingosine 1-phosphate (S1P) Ⅲ sphingosine kinase (Sphk) Ⅲ S1P lyase (Sgpl) Ⅲ plasma S1P gradient Ⅲ Shear stress T he bioactive lipid sphingosine 1-phosphate (S1P) is a potent regulator of numerous biological responses, the most well characterized being cardiovascular and immune effects. S1P binds to and activates a widely expressed family of G protein-coupled receptors, termed S1PRs. Intracellular signaling of these receptors are thought to mediate most of the effects of S1P. [1][2][3][4] S1P is abundant (0.1 to 1.2 mol/L) in plasma, where it is mainly bound to albumin and high-density lipoprotein (HDL). 5,6 Thus, S1P receptors on blood-borne cells are likely to be constitutively activated. In contrast, S1P levels in tissues are considerably lower (0.5 to 75 pmol/mg wet weight), although tissues with high blood content, such as spleen, are exceptions. This concentration difference of S1P between plasma and tissues has been termed the vascular S1P gradient, which was shown to be functionally important in lymphocyte egress from the lymphoid tissues and the thymus. 7,8 The regulation of S1P production and release is not well understood. Secretion of S1P is observed in a variety of cells including platelets, 9 -11 erythrocytes, 9,12,13 mononuclear cells, neutrophils, 9 mast cells, 14,15 and endothelial cells. 16 The concentration of S1P in the cell is determined by the activity of biosynthetic enzymes (sphingosine kinase [Sphk]-1 and -2) and the degradative ...

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Section: Shear Stress Induces S1p Release By Endothelial Cellsmentioning

confidence: 99%

Vascular Endothelium As a Contributor of Plasma Sphingosine 1-Phosphate

Venkataraman

Lee

Michaud

et al. 2008

Circulation Research

429

421

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“…Caveolae have also been found to initiate TNFα-mediated apoptosis [224]. Neutral (but not acidic) sphingomyelinase activity is mechanically potentiated by increased vascular flow and could specifically be inhibited by a peptide that corresponds to the Cav1 CSD [223] or by scyphostatin, which specifically blocks neutral but not acid sphingomyelinase [225,226]. Cav1 interacts directly with PI3K that participates in the well-known phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway, and its overexpression sensitizes fibroblasts to ceramide-induced death [227].…”

Section: Role Of Cav1 In Cell Death and Survivalmentioning

confidence: 99%

Caveolin-1 in tumor progression: the good, the bad and the ugly

Goetz

Lajoie

Wiseman

et al. 2008

Cancer Metastasis Rev

273

261

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Caveolin-1 (Cav1) is a multifunctional scaffolding protein with multiple binding partners that is associated with cell surface caveolae and the regulation of lipid raft domains. Cav1 regulates multiple cancer-associated processes including cellular transformation, tumor growth, cell migration and metastasis, cell death and survival, multidrug resistance and angiogenesis. However, Cav1 has been reported to impact both positively and negatively on various aspects of tumor progression and while reported to function as a tumor suppressor, it has also been identified as a poor prognostic factor in various human cancers. In this review, we survey the functional roles of Cav1 in cancer and argue that Cav1 function is interdependent on tumor stage and the expression of molecular effectors that impact on its role during tumor progression.

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“…4 which demonstrate that the inhibition of endothelial NO formation by PAF is abrogated in isolated perfused lungs of mice deficient in ASM (Asm -/-). Once again the signaling events in endothelial cells of the systemic circulation are diametrically opposed to those in the lung, in that ceramide activates eNOS and stimulates endothelial NO formation in cultured bovine aortic endothelial cells (BAEC) [53,54], as well as in eNOS expressing chinese hamster ovary (CHO) cells [55,56]. Notably, the ceramide-induced stimulation of eNOS in systemic endothelial cells is independent of Ca 2+ -regulated pathways since it is unaffected by the intracellular Ca ] i signal [54], and likewise seems to be independent of the source of ceramide, as it is equally triggered by stimulation of both ASM and neutral sphingomyelinase (NSM) [57].…”

Section: Regulation Of Endothelial No Synthesis By Sphingomyelinase Amentioning

confidence: 99%

Vascular Barrier Regulation by PAF, Ceramide, Caveolae, and NO - an Intricate Signaling Network with Discrepant Effects in the Pulmonary and Systemic Vasculature

Kuebler

Yang

Samapati

et al. 2010

Cell Physiol Biochem

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Increased endothelial permeability and vascular barrier failure are hallmarks of inflammatory responses in both the pulmonary and the systemic circulation. Platelet-activating factor (PAF) has been implicated as an important lipid mediator in the formation of pulmonary and extrapulmonary edema. Ostensibly, the PAF-induced signaling pathways in endothelial cells utilize similar structures and molecules including acid sphingomyelinase, ceramide, caveolae, endothelial nitric oxide synthase, and nitric oxide, in pulmonary and systemic microvessels. Yet, the constituents of these signaling pathways act and respond in distinctly different and frequently opposing ways in the lung versus organs of the systemic circulation. By confronting seemingly discrepant findings from the literature, we reconstruct the differential signaling pathways by which PAF regulates edema formation in the systemic and the pulmonary vascular bed, and trace this dichotomy from the level of myosin light chain kinase via the regulation of endothelial nitric oxide synthase and sphingomyelinase signaling to the level of caveolar trafficking. Here, we propose that PAF regulates vascular barrier function in individual organs by opposing signaling pathways that culminate in increased respectively decreased nitric oxide synthesis in the systemic and the pulmonary endothelium. The present review may provide a physiological explanation for the overall disappointing results of previous pharmacological strategies in conditions of generalized barrier failure such as sepsis, and instead advertises the development of organ-specific interventions by targeting the individual composition or trafficking of endothelial caveolae.

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Neutral sphingomyelinase inhibitor scyphostatin prevents and ceramide mimics mechanotransduction in vascular endothelium

Cited by 63 publications

References 49 publications

Vascular Endothelium As a Contributor of Plasma Sphingosine 1-Phosphate

Vascular Endothelium As a Contributor of Plasma Sphingosine 1-Phosphate

Caveolin-1 in tumor progression: the good, the bad and the ugly

Vascular Barrier Regulation by PAF, Ceramide, Caveolae, and NO - an Intricate Signaling Network with Discrepant Effects in the Pulmonary and Systemic Vasculature

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