Sphingomyelinase causes endothelium‐dependent vasorelaxation through endothelial nitric oxide production without cytosolic Ca<sup>2+</sup> elevation

Mogami, Kimiko; Kishi, Hiroko; Kobayashi, Sei

doi:10.1016/j.febslet.2004.11.100

Cited by 27 publications

(23 citation statements)

References 24 publications

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“…In Fabry disease, there is a suggestion that the clinical abnormalities are caused by perturbations of extralysosomal functions. Excess amounts of Gb 3 in the cell membrane may interfere with the function of caveolae/rafts that are known to contain glycosphingolipids and a number of important signal transduction proteins such as endothelial nitric oxide synthase (eNOS) [26]. There is evidence of increased reactive oxygen species in Fabry disease, possibly in relation to eNOS [1,4,27], as well as an abnormality of the fibrinolytic system [28].…”

Section: Discussionmentioning

confidence: 98%

Cellular and tissue localization of globotriaosylceramide in Fabry disease

et al. 2007

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The pathogenesis of Fabry disease is poorly understood. We used a variety of immunohistological techniques to localize globotriaosylceramide, the main glycolipid that accumulates in Fabry disease. Globotriaosylceramide immunoreactivity in a heterogenous pattern was present in all organs examined of a patient on long-term enzyme replacement therapy. In the brain, immmunopositivity was found only in the parahippocampal region. Globotriaosylceramide immunostaining was present in the cell membrane and cytoplasm of endothelial cells, even in the absence of lysosomal inclusions. In kidney tissue, globotriaosylceramide colocalized with lysosomal, endoplasmic reticulum, and nuclear markers. Pre- and postembedding immunogold electron microscopy of skin biopsies and untreated patient cultured skin fibroblasts confirmed the presence of globotriaosylceramide in the cell membrane, in various cytoplasmic structures, and in the nucleus. Control organ tissues and cultured fibroblasts from five unaffected subjects were uniformly negative for globotriaosylceramide by immunohistochemistry and immunogold electron microscopy. We conclude that a substantial amount of lysosomal and extralysosomal globotriaosylceramide immunoreactivity remains in cells and tissues even after years of enzyme replacement therapy in Fabry disease. These findings are crucial for the understanding of the disease mechanism and suggest the usefulness of immunostaining for globotriaosylceramide as a means to assess response to novel, specific therapies.

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Section: Discussionmentioning

confidence: 98%

Cellular and tissue localization of globotriaosylceramide in Fabry disease

et al. 2007

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“…In nonmuscle cells, ceramide enhances ROS production by mitochondria (7,16) and NADPH oxidase (54) and also stimulates NO synthesis (2,31). SMase acts on vascular endothelial cells to increase NO production via the endothelial isoform of NO synthase (31).…”

Section: Discussionmentioning

confidence: 99%

Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Ferreira

Moylan

Gilliam

et al. 2010

American Journal of Physiology-Cell Physiology

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Sphingomyelinase (SMase) hydrolyzes membrane sphingomyelin into ceramide, which increases oxidants in nonmuscle cells. Serum SMase activity is elevated in sepsis and heart failure, conditions where muscle oxidants are increased, maximal muscle force is diminished, and fatigue is accelerated. We tested the hypotheses that exogenous SMase and accumulation of ceramide in muscle increases oxidants in muscle cells, depresses specific force of unfatigued muscle, and accelerates the fatigue process. We also anticipated that the antioxidant N-acetylcysteine (NAC) would prevent SMase effects on muscle function. We studied the responses of C2C12 myotubes and mouse diaphragm to SMase treatment in vitro. We observed that SMase caused a 2.8-fold increase in total ceramide levels in myotubes. Exogenous ceramide and SMase elevated oxidant activity in C2C12 myotubes by 15-35% (P < 0.05) and in diaphragm muscle fiber bundles by 58-120% (P < 0.05). The SMase-induced increase in diaphragm oxidant activity was prevented by NAC. Exogenous ceramide depressed diaphragm force by 55% (P < 0.05), while SMase depressed maximal force by 30% (P < 0.05) and accelerated fatigue--effects opposed by treatment with NAC. In conclusion, our findings suggest that SMase stimulates a ceramide-oxidant signaling pathway that results in muscle weakness and fatigue.

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“…dissociation of eNOS from the plasma membrane and calveolin; and 2). activation of eNOS via phosphorylation [71,72]. The exact reasons for these controversial results from different reports are not clear.…”

Section: Ceramide Smase and Nitric Oxide (No)mentioning

confidence: 97%

Ceramide: A common pathway for atherosclerosis?

et al. 2008

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Plasma sphingomyelin concentration is correlated with the development of atherosclerosis. It has been found to exist in significantly higher concentrations in aortic plaque. This appears to have clinical relevance as well as it has been shown to be an independent predictor of coronary artery disease. Ceramide, the backbone of sphingolipids, is the key component which affects atherosclerotic changes through its important second-messenger role. This paper sheds light on some of the current literature supporting the significance of ceramide with respect to its interactions with lipids, inflammatory cytokines, homocysteine and matrix metalloproteinases. Furthermore, the potential therapeutic implications of modulating ceramide concentrations are also discussed.

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Sphingomyelinase causes endothelium‐dependent vasorelaxation through endothelial nitric oxide production without cytosolic Ca²⁺ elevation

Cited by 27 publications

References 24 publications

Cellular and tissue localization of globotriaosylceramide in Fabry disease

Cellular and tissue localization of globotriaosylceramide in Fabry disease

Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Ceramide: A common pathway for atherosclerosis?

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Sphingomyelinase causes endothelium‐dependent vasorelaxation through endothelial nitric oxide production without cytosolic Ca2+ elevation

Cited by 27 publications

References 24 publications

Cellular and tissue localization of globotriaosylceramide in Fabry disease

Cellular and tissue localization of globotriaosylceramide in Fabry disease

Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Ceramide: A common pathway for atherosclerosis?

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Sphingomyelinase causes endothelium‐dependent vasorelaxation through endothelial nitric oxide production without cytosolic Ca²⁺ elevation