Disease relevance of Smpd2

• Comparative kinetic analyses of the neutral sphingomyelinase in the cells under normoxia and hypoxia showed that hypoxia increased Vmax but did not affect Km of the enzyme [1].
• It has been reported that, in rat liver or in ascites hepatoma AH7974, high activity of neutral sphingomyelinase (SMase) is found at the plasma membrane, with a lesser but significant amount in nucleus and cytoplasm [2].
• To examine the intracellular localization of neutral sphingomyelinase 1 (nSMase 1), a rabbit polyclonal antibody was raised against a recombinant form of the enzyme expressed in E. coli [2].
• Furthermore, genetic knockdown of nSMase by an antisense strategy rendered C6 glioma cells specifically resistant to Abeta25-35 cytotoxicity without affecting their vulnerability to serum deprivation [3].
• These results suggest that N-SMase is a key component of the signaling pathways in cytokine- and other stress-induced cellular responses, and that inhibiting or stopping N-SMase activity is an important strategy to prevent neuron death from ischemia [4].

High impact information on Smpd2

• In addition, Abeta activated neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase, resulting in increased ceramide generation [5].
• Glutathione (GSH) precursors inhibited Abeta activation of nSMase and prevented OLG death, whereas GSH depletors increased nSMase activity and Abeta-induced death [5].
• Blocking ceramide degradation with N-oleoyl-ethanolamine exacerbated Abeta cytotoxicity; and addition of bacterial sphingomyelinase (mimicking cellular nSMase activity) induced OLG death [5].
• The apoptotic response was FAS receptor- and neutral sphingomyelinase-dependent and independent of FAS ligand expression, and neither chelation of intracellular and extracellular Ca(2+) nor down-regulation of PKC expression altered the apoptotic effects of bile acids [6].
• We postulate a novel physiological function for neutral sphingomyelinase as a new mechanosensor initiating the ERK cascade and possibly other mechanotransduction pathways [7].

Chemical compound and disease context of Smpd2

• Pretreatment of cells with exogenous GSH or NAC resulted in inhibition of both neutral sphingomyelinase (SMase) activation and ceramide formation during hypoxia [8].

Biological context of Smpd2

• Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase [9].
• In PC12 cells overexpressing Bcl-2 which show strong resistance to hypoxia, sphingomyelin hydrolysis was decreased and activation of neutral sphingomyelinase was reduced [1].
• During liver regeneration, an increase in chromatin cholesterol is observed between 6 and 18 h after hepatectomy, when the neutral-sphingomyelinase activity increases and the sphingomyelin-synthase is inhibited [10].
• Prior to the onset of apoptosis, the activity of neutral sphingomyelinase increased in the nuclei of hepatocytes in ligated lobes (30 min after the ligation) [11].
• Our results suggest that ceramide generated by nSMase may be a critical mediator in the regulation of iNOS gene expression via ras-mediated NF-kappaB activation under inflammatory conditions [12].

Anatomical context of Smpd2

• Transient mechanoactivation of neutral sphingomyelinase in caveolae to generate ceramide [7].
• This acute mechanoactivation occurs directly at the luminal endothelial cell surface primarily in caveolae enriched in sphingomyelin and neutral sphingomyelinase, but not acid sphingomyelinase [7].
• These protective effects were accompanied by significant inhibition of cytochrome c release from mitochondria and caspase 9 activation, therefore localizing N-SMase activation upstream of mitochondrial dysfunction [9].
• A novel magnesium-independent neutral sphingomyelinase associated with rat central nervous system meylin [13].
• The results indicate that nSMase 1 mainly resides in the nucleus and may thus differ from neutral SMase in plasma membrane [2].

Associations of Smpd2 with chemical compounds

• To prevent degradation of the newly synthesized SM to ceramide, all experiments were performed in the presence of EDTA to minimize neutral sphingomyelinase activity and at neutral pH to minimize acid sphingomyelinase activity [14].
• The biochemical properties, dithiothreitol requirement and high salt concentration dependency, of cloned and expressed nSMase 1 resemble those of previously described nuclear neutral SMase of AH7974 [2].
• Neutral sphingomyelinase (SMase) activity in muscle of fatty rats was two times higher than that in lean rats and was lowered to the level of that in lean rats by 4 days' pioglitazone administration [15].
• Removal of the nuclear envelope by treatment with Triton X-100 did not significantly decrease the amount of nuclear nSMase 1, and western blotting of subnuclear fractions (i.e. nuclear envelope, chromatin, and nuclear matrix) revealed nSMase 1 signal exclusively in the nuclear matrix [2].
• Inhibition of the SM-Cer cascade either by vitamin E treatment or by the neutral sphingomyelinase inhibitor 3-O-methyl sphingomyelin also resulted in alteration of the transcriptional binding activities of C/EBP, NFkappaB, AP-1, and CREB in C6 glial cells [16].

Regulatory relationships of Smpd2

• Similar to exogenously added ceramide, also interleukin-1beta which is an established activator of the neutral sphingomyelinase that leads to endogenous ceramide formation upregulates LIMK-1 protein expression and activity [17].

Other interactions of Smpd2

• Abeta, TNF-alpha, or the combination of both, increased neutral sphingomyelinase (nSMase) activity, but not acidic sphingomyelinase (aSMase) activity, leading to ceramide accumulation [18].
• Overexpression of a truncated mutant of nSMase with a dominant negative function inhibited iNOS mRNA production [18].
• Ganglioside GM1 potentiates the effect of IL-1 beta on neutral sphingomyelinase activity in rat brain synaptosomes [19].
• Neutral sphingomyelinase activity was induced with similar kinetics, and both activities remained elevated for several hours. c-Jun N-terminal kinase (JNK) was also activated within the same time frame [20].

Analytical, diagnostic and therapeutic context of Smpd2

• On gel-filtration column chromatography of nuclear extract, the profile of neutral SMase activity corresponded well with immunoreactive protein bands on western blotting, suggesting that a large part of nuclear neutral SMase may be nSMase 1 [2].
• Moreover, immuno-electron microscopy clearly showed the signal of nSMase 1 to be more dense in the nucleus than in the cytoplasm of AH7974 [2].
• Immunocytochemistry with AH7974, as well as rat fibroblast cell line 3Y1, demonstrated nSMase 1 to be localized mainly in the nucleus, with some in the cytoplasm [2].
• Semiquantitative PCR analysis indicated that neutral sphingomyelinase mRNA may be reduced in SHR VSMC [21].
• The single band obtained for each enzyme on SDS-PAGE was identified as an antigen with antibody raised against the purified neutral sphingomyelinase [22].

References