Background—
The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation.
Methods and Results—
We generated CD137-deficient apolipoprotein E–knockout mice (
ApoE
−/−
CD137
−/−
) and LDL-receptor–knockout mice (
Ldlr
−/−
CD137
−/−
) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-γ, monocyte chemoattractant protein-1, and tumor necrosis factor-α. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels.
Conclusions—
CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.
A presynaptic membrane disturbance is an essential process for the release of various neurotransmitters. Ceramide, which is a tumor suppressive lipid, has been shown to act as a channel-forming molecule and serve as a precursor of ceramide-1-phosphate, which can disturb the cellular membrane. This study found that while permeable ceramide increases the rate of dopamine release in the presence of a Ca 2+ -ionophore, A23187, permeable ceramide-1-phosphate provoked its release even without the ionophore. The treatment of PC12 cells with the ionophore at concentrations < 2 lM produced ceramide via the sphingomyelin (SM) pathway with a concomitant release of dopamine, and no cell damage was observed. The addition of a Ca 2+ chelator, EGTA, to the medium inhibited the increase in the release of both the ceramide and dopamine. This suggests that ceramide might be produced by Ca 2+ and is implicated in the membrane disturbance associated with the release of dopamine as a result of its conversion to ceramide-1-phosphate. Consistent with these results, this study detected a membrane-associated and neutral pH optimum sphingomyelinase (SMase) whose activity was increased by Ca
2+. Together, these results demonstrate that ceramide can be produced via the activation of a neutral form of SMase through Ca The release of neurotransmitters from specialized active zones in the presynaptic terminals is a key step in synaptic transmission. The release of the synaptic vesicles containing neurotransmitter is triggered within 200 ls of the depolarization of a nerve terminal as a result of the influx of Ca 2+ through the voltage-gated Ca 2+ channels, which increases the local Ca 2+ concentration from a basal level of 100 nM to > 100 lM (Smith and Augustine 1988). This depolarizationinduced Ca 2+ influx leads to the fusion of the synaptic vesicles docked at the active zone for the release of neurotransmitters (Augustine et al. 1987). While a number of proteins have been identified and suggested to participate in the assembly and subsequent disengagement of a vesicledocking complex for fusion, the mechanism that ultimately triggers this neuroexocytosis is unknown.Recent studies have shown that soluble N-ethylmaleimidesensitive factor-attachment-protein-receptors (SNAREs) are formed in a Ca 2+ -dependent manner via synaptic vesicle VAMP (synaptobrevin), plasma membrane syntaxin and SNAP-25 (Sollner et al. 1993). Together with synaptotagmin as a Ca 2+ sensor, they form the core complex suggested to coordinate the regulated vesicular fusion for neurotransmitter release (Brose et al. 1992). SNAREs are targets for potent neurotransmission inhibitors including botulinum and tetanus toxins (Sudhof et al. 1993). These toxins selectively inhibit the synaptic vesicle fusion via site-specific proteolysis Abbreviations used: AA, arachidonic acid; cPLA 2 , cytosolic phopholipase A2; DMSO, dimethylsulfoxide; FB 1 , fumonisin B1; FPLC, fast protein liquid chromatography; MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; N-SMase...
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