Sphingomyelinase D/Ceramide 1-Phosphate in Cell Survival  and Inflammation

Rivera, Io-Guané; Ordoñez, Marta; Presa, Natalia; Gómez-Larrauri, Ana; Simón, Jorge; Trueba, Miguel; Gómez-Muñoz, Antonio

doi:10.3390/toxins7051457

Cited by 49 publications

(33 citation statements)

References 48 publications

(80 reference statements)

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“…Previous studies associate EP receptors with the BBB (McCullough et al, 2004;Pekcec et al, 2009;Jiang and Dingledine, 2013). EP2, in particular, shares biologic characteristics with C1P; both EP2 and C1P have been implicated with decreased apoptosis, increased angiogenesis, and the promotion of inflammatory responses through COX-2 (Sung et al, 2005;Kamiyama et al, 2006;Liang et al, 2008;Kim et al, 2013;Rivera et al, 2015). Our results show that EP2 exists almost exclusively on the luminal membrane of rat brain capillaries, suggesting that in our model PGE 2 activates its receptor in the capillary lumen.…”

Section: Discussionsupporting

confidence: 64%

Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling

2017

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P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our laboratory has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycoprotein transport activity. Here, we investigated the potential for another sphingolipid, ceramide 1-phosphate (C1P), to modulate efflux pumps at the BBB. Using confocal microscopy and measuring luminal accumulation of fluorescent substrates, we assessed the transport activity of several efflux pumps in isolated rat brain capillaries. C1P treatment induced P-glycoprotein transport activity in brain capillaries rapidly and reversibly. In contrast, C1P did not affect transport activity of two other major efflux transporters, multidrug resistance protein 2 and breast cancer resistance protein. C1P induced P-glycoprotein transport activity without changing transporter protein expression. Inhibition of the key signaling components in the cyclooxygenase-2 (COX-2)/prostaglandin E2 signaling cascade (phospholipase A2, COX-2, multidrug resistance protein 4, and G-protein-coupled prostaglandin E2 receptors 1 and 2), abolished P-glycoprotein induction by C1P. We show that COX-2 and prostaglandin E2 are required for C1P-mediated increases in P-glycoprotein activity independent of transporter protein expression. This work describes how C1P activates a signaling cascade to dynamically regulate P-glycoprotein transport at the BBB and offers potential clinical targets to modulate neuroprotection and drug delivery to the CNS.

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Section: Discussionsupporting

confidence: 64%

Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling

2017

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“…Numerous studies support the antiapoptotic effect of C1P in different cell types. In macrophages and keratinocytes, higher levels of endogenous C1P (after CERK activity upregulation) blocked apoptosis, 12,21 whereas the exogenous addition of C1P to cochlear hair cell and retina photoreceptor cultures also increases cell survival. 13,14 In line with this evidence, we here demonstrated that C1P protects ECFC not only from apoptosis but also from necrosis triggered by 2 molecules highly elevated in the ischemic tissue like TNFα and monosodium urate crystal, respectively.…”

Section: Discussionmentioning

confidence: 99%

Ceramide 1-Phosphate Protects Endothelial Colony–Forming Cells From Apoptosis and Increases Vasculogenesis In Vitro and In Vivo

Mena

Zubiry

Dizier

et al. 2019

ATVB

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Ceramide 1-phosphate (C1P) is a bioactive sphingolipid highly augmented in damaged tissues. Because of its abilities to stimulate migration of murine bone marrow-derived progenitor cells, it has been suggested that C1P might be involved in tissue regeneration. In the present study, we aimed to investigate whether C1P regulates survival and angiogenic activity of human progenitor cells with great therapeutic potential in regenerative medicine such as endothelial colonyforming cells (ECFCs). APPROACH AND RESULTS: C1P protected ECFC from TNFα (tumor necrosis factor-α)-induced and monosodium urate crystalinduced death and acted as a potent chemoattractant factor through the activation of ERK1/2 (extracellular signal-regulated kinases 1 and 2) and AKT pathways. C1P treatment enhanced ECFC adhesion to collagen type I, an effect that was prevented by β1 integrin blockade, and to mature endothelial cells, which was mediated by the E-selectin/CD44 axis. ECFC proliferation and cord-like structure formation were also increased by C1P, as well as vascularization of gel plug implants loaded or not with ECFC. In a murine model of hindlimb ischemia, local administration of C1P alone promoted blood perfusion and reduced necrosis in the ischemic muscle. Additionally, the beneficial effects of ECFC infusion after ischemia were amplified by C1P pretreatment, resulting in a further and significant enhancement of leg reperfusion and muscle repair. CONCLUSIONS: Our findings suggest that C1P may have therapeutic relevance in ischemic disorders, improving tissue repair by itself, or priming ECFC angiogenic responses such as chemotaxis, adhesion, proliferation, and tubule formation, which result in a better outcome of ECFC-based therapy (Visual Overview).

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“…The sphingolipid ceramide has been shown to trigger apoptosis in a wide variety of cells . Ceramide induced cell death involves mitochondria .…”

Section: Introductionmentioning

confidence: 99%

Ceranib‐2‐induced suicidal erythrocyte death

Signoretto

Zierle

Bhuyan

et al. 2016

Cell Biochemistry & Function

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Ceramide is known to trigger apoptosis of nucleated cells and eryptosis of erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Besides ceramide, stimulators of eryptosis include increase of cytosolic Ca(2+) -activity ([Ca(2+) ]i ) and oxidative stress. Ceramide is degraded by acid ceramidase and inhibition of the enzyme similarly triggers apoptosis. The present study explored, whether ceramidase inhibitor Ceranib-2 induces eryptosis. Flow cytometry was employed to quantify phosphatidylserine-exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca(2+) ]i from Fluo3-fluorescence, reactive oxygen species (ROS) from DCF dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. A 48 h exposure of human erythrocytes to Ceranib-2 significantly increased the percentage of annexin-V-binding cells (≥50 μM) and the percentage of hemolytic cells (≥10 μM) without significantly modifying forward scatter. Ceranib-2 significantly increased Fluo3-fluorescence, DCF fluorescence and ceramide abundance. The effect of Ceranib-2 on annexin-V-binding was not significantly blunted by removal of extracellular Ca(2+) . Ceranib-2 triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to increase of ceramide abundance and induction of oxidative stress, but not dependent on Ca(2+) entry. Copyright © 2016 John Wiley & Sons, Ltd.

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Sphingomyelinase D/Ceramide 1-Phosphate in Cell Survival and Inflammation

Cited by 49 publications

References 48 publications

Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling

Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling

Ceramide 1-Phosphate Protects Endothelial Colony–Forming Cells From Apoptosis and Increases Vasculogenesis In Vitro and In Vivo

Ceranib‐2‐induced suicidal erythrocyte death

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