Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells

Loidl, Alexandra; Claus, Ralf A.; Ingoliç, Elisabeth; Deigner, Hans‐Peter; Hermetter, Albin

doi:10.1016/j.bbadis.2004.06.003

Cited by 39 publications

(34 citation statements)

References 38 publications

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“…These lipids have been found to induce apoptotic signalling pathways by the activation of sphingomyelinase and, in particular, the acid form of the enzyme which is known to be involved in the earlier stages of apoptosis resulting in phosphorylation of mitogen activated protein kinase (MAPK) and caspase 3 signalling [47,48]. A biphasic response of oxidized phospholipids has been reported previously with proliferation occurring at low concentration and apoptosis predominating at high concentrations [27,29].…”

Section: Discussionmentioning

confidence: 92%

Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

et al. 2015

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The presence of inflammatory cells and MPO (myeloperoxidase) in the arterial wall after vascular injury could increase neointima formation by modification of phospholipids. The present study investigates how these phospholipids, in particular oxidized and chlorinated species, are altered within injured vessels and how they affect VSMC (vascular smooth muscle cell) remodelling processes. Vascular injury was induced in C57BL/6 mice and high fat-fed ApoE −/− (apolipoprotein E) mice by wire denudation and ligation of the left carotid artery (LCA). Neointimal and medial composition was assessed using immunohistochemistry and ESI-MS. Primary rabbit aortic SMCs (smooth muscle cells) were utilized to examine the effects of modified lipids on VSMC proliferation, viability and migration at a cellular level. Neointimal area, measured as intima-to-media ratio, was significantly larger in wire-injured ApoE −/− mice (3.62 + − 0.49 compared with 0.83 + − 0.25 in C57BL/6 mice, n = 3) and there was increased oxidized low-density lipoprotein (oxLDL) infiltration and elevated plasma MPO levels. Relative increases in lysophosphatidylcholines and unsaturated phosphatidylcholines (PCs) were also observed in wire-injured ApoE −/− carotid arteries. Chlorinated lipids had no effect on VSMC proliferation, viability or migration whereas chronic incubation with oxidized phospholipids stimulated proliferation in the presence of fetal calf serum [154.8 + − 14.2 % of viable cells at 1 μM PGPC (1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine) compared with control, n = 6]. In conclusion, ApoE −/− mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect.

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Section: Discussionmentioning

confidence: 92%

Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

et al. 2015

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“…Involvement of MAPK subfamilies (P44/42 MAP kinase, c-JNK, and p38 kinase) in ceramide-induced apoptosis have been reported in various cell types, including astrocytes (Blazquez et al 2000, Oh et al 2006, neuronal cells (Verheij et al 1996, Willaime et al 2001, Willaime-Morawek et al 2003, lung cancer-derived cells (Kurinna et al 2004) and vascular smooth muscle cells (Loidl et al 2004). The P44/42 MAP kinase pathway plays a major role in regulating cell growth, survival and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

MacRae¹,

Burdon²,

Ahmed³

et al. 2006

Journal of Endocrinology

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Proinflammatory cytokines inhibit growth plate development. However, their underlying mechanisms of action are unclear. These effects may be mediated by ceramide, a sphingosine-based lipid second messenger, which is elevated in a number of chronic inflammatory diseases. To test this hypothesis, we determined the effects of C2-ceramide, a cell permeable ceramide analogue, on the growth of the ATDC5 chondrogenic cell line and on cultured fetal mice metatarsals. In ATDC5 cells, C2-ceramide significantly induced apoptosis at both 40 (82%; P!0 . 05) and 25 mM (53%; P!0 . 05). At 40 mM, C2-ceramide significantly reduced proliferation ([ 3 H]-thymidine uptake/mg protein) (62%; P!0 . 05). C2-ceramide did not markedly alter the differentiation state of the cells as judged by the expression of markers of chondrogenesis and differentiation (sox 9, collagen II and collagen X). The IGF-I signalling pathway is the major autocrine/paracrine regulator of bone growth. Both in the presence and absence of IGF-I, C2-ceramide (25 mM) induced an equivalent reduction in proliferation (60%; P!0 . 001). Similarly, C2-ceramide (40 mM) induced a 31% reduction in fetal metatarsal growth both in the presence and absence of IGF-I (both P!0 . 001). Furthermore, C2-ceramide reduced ADCT5 proliferation in the presence of AG1024, an IGF-I and insulin receptor blocker. Therefore, C2-ceramide-dependent inhibition appears to be independent of IGF-mediated stimulation of bone growth. Indeed, biochemical studies demonstrated that C2-ceramide (25 mM) pretreatment did not alter IGF-I-stimulated phosphorylation of insulin receptor substrate-1, Akt or P44/42 MAP kinase. In conclusion, C2-ceramide inhibits proliferation and induces apoptosis in growth plate chondrocytes through an IGF-I independent mechanism.

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“…Thereby, the role of NOX1 and its associated activities NOX1 organizer and NOX1 activator (32) were confirmed. Most likely, lipid peroxides generated through the action of hydroxyl radicals activate SMAse (33,34). The strong effect of the knockdown of SMAse indicates that ceramides might indeed play a crucial role in intracellular signalling pathways after ROS/RNS-dependent extracellular effects.…”

Section: (Siduox1) Inducible No Synthase (Siinos) Transforming Growmentioning

confidence: 99%

Central Signaling Elements of Intercellular Reactive Oxygen/Nitrogen Species-dependent Induction of Apoptosis in Malignant Cells

Bauer

2017

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Abstract. Intercellular reactive oxygen/reactive nitrogen species-(ROS/RNS)-dependent induction of apoptosis in malignant cells is discussed as a potential control step during oncogenesis. In previous studies, the mechanism of intercellular apoptosis-inducing signaling was mainly established throughSelective induction of apoptosis in transformed cells is established either through their interaction with neighboring non-transformed cells or through autocrine apoptotic selfdestruction (1-3). Thereby, the HOCl (2, 5) and the nitric oxide/peroxynitrite (NO/PON) signaling pathways (2, 5, 6) are the dominant intercellular apoptosis-inducing signaling pathways [reviewed in (5)]. Both pathways are driven by superoxide anions which are generated by membraneassociated NADPH oxidase-1 (NOX1) of malignant cells (4, 7) and result in the generation of hydroxyl radicals that induce apoptosis through lipid peroxidation in the cell membrane (8).Mechanisms and the multiple modes of interaction of these pathways have been elucidated through inhibitor and reconstitution experiments [reviewed in (4, 5, 9)].Elimination of transformed cells through selective apoptosis induction mediated by intercellular reactive oxygen species (ROS)-dependent signaling has been discussed as a potential natural tumor-preventive mechanism (4, 10, 11). This concept is in agreement with the pioneering work of Deichman et al. , who have shown that tumor progression requires establishment of resistance to H 2 O 2 (12, 13). Resistance is achieved through the expression of membraneassociated catalase (8,14,15). Catalase interferes with the HOCl signaling pathway through decomposition of H 2 O 2 and with NO/PON signaling through oxidation of NO and decomposition of PON (5,8,16,17). Recent quantitative characterization of membrane-associated catalase has shown that localization of catalase on the outside of cells is already associated with the transformed state of the cells, however, at a concentration that is not sufficient to prevent intercellular ROS-dependent signaling (15). Catalase seems to be released by tumor cells and is covalently attached to the cells through the action of transglutaminase-2 (15).In addition to membrane-associated catalase, tumor cells also carry superoxide dismutase (SOD) on their membrane. SOD has a co-modulatory role through preventing superoxide anion-dependent inhibition of catalase (9, 18).The functional complex of membrane-associated NOX1 and protective catalase and SOD represents a regular characteristic of tumor cells and therefore is a focus for the establishment of novel therapeutic approaches (18)(19)(20). The complex signaling chemistry of transformed cells, or tumor cells after inhibition of their membrane-associated catalase, has, so far, been mainly elucidated through inhibitor studies and reconstitution experiments. Small interfering ribonucleic acid (siRNA)-based knockdown of defined 499

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Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells

Cited by 39 publications

References 38 publications

Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

Central Signaling Elements of Intercellular Reactive Oxygen/Nitrogen Species-dependent Induction of Apoptosis in Malignant Cells

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