Neutral sphingomyelinase: past, present and future

被引:64
作者
Chatterjee, S [1 ]
机构
[1] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA
关键词
atherosclerosis; apoptosis; cell proliferation; sterol homeostasis; signal transduction;
D O I
10.1016/S0009-3084(99)00077-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sphingomyelin and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. At the epicenter of the sphingomyelin - cell signaling pathway is a family of phospholipases called sphingomyelinases. These enzymes cleave sphingomyelin to produce ceramide and phosphocholine. Ceramide in turn serves as a lipid second messenger that induces a variety of cell regulatory phenomenon such as programmed cell death (apoptosis), cell differentiation, cell proliferation, and sterol homeostasis. Neutral sphingomyelinase (N-SMase) is a Mg2+ sensitive enzyme that can be activated by a host of physiologically relevant and structurally diverse molecules like tumor necrosis factor-alpha (TNF-alpha), oxidized human low density lipoproteins (Ox-LDL), and several growth factors. Large amounts of ceramide accumulate in human fatty streaks and plaques along with Ox-LDL, growth factors, and proinflammatory cytokines in human atherosclerosis. A further role of ceramide and N-SMase in atherosclerosis was uncovered by the finding that Ox-LDL and TNF-alpha stimulated N-SMase activity. In turn, ceramide and/or a homolog serves as an important stress signaling molecule in signal transduction, which leads to apoptosis. Interestingly, an antibody against N-SMase can abrogate Ox-LDL and TNF-alpha induced apoptosis, and therefore may be useful for additional studies of apoptosis in experimental animals. Overexpression of recombinant human N-SMase in human aortic smooth muscle cells markedly stimulate apoptosis, presumably via the multioligomerization of the 'death domain'. Since plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke and heart failure. In contrast to these observations in human hepatocytes, TNF-alpha mediated N-SMase activation did not induce apoptosis. Rather it stimulated the maturation of sterol regulatory element (SRE) binding protein (SREBP-1). Moreover, a cell permeable ceramide was found to reconstitute the phenomenon above in a sterol-independent fashion. These findings provide alternate avenues for therapy of patients with hypercholesterolemia and atherosclerosis. The findings reported here suggests that N-SMase plays important cell regulatory roles and provide an exciting opportunity to further these findings to understand the pathophysiology of human disease states. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.
引用
收藏
页码:79 / 96
页数:18
相关论文
共 85 条
  • [41] Daunorubicin-induced apoptosis: Triggering of ceramide generation through sphingomyelin hydrolysis
    Jaffrezou, JP
    Levade, T
    Bettaieb, A
    Andrieu, N
    Bezombes, C
    Maestre, N
    Vermeersch, S
    Rousse, A
    Laurent, G
    [J]. EMBO JOURNAL, 1996, 15 (10) : 2417 - 2424
  • [42] INDUCTION OF APOPTOTIC DNA-DAMAGE AND CELL-DEATH BY ACTIVATION OF THE SPHINGOMYELIN PATHWAY
    JARVIS, WD
    KOLESNICK, RN
    FORNARI, FA
    TRAYLOR, RS
    GEWIRTZ, DA
    GRANT, S
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (01) : 73 - 77
  • [43] JAYADEV S, 1994, J BIOL CHEM, V269, P5757
  • [44] Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knockout mice reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase
    Jeong, TS
    Schissel, SL
    Tabas, I
    Pownall, HJ
    Tall, AR
    Jiang, XC
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (04) : 905 - 912
  • [45] KIM MY, 1991, J BIOL CHEM, V266, P484
  • [46] Modified low density lipoprotein delivers substrate for ceramide formation and stimulates the sphingomyelin-ceramide pathway in human macrophages
    Kinscherf, R
    Claus, R
    Deigner, HP
    Nauen, O
    Gehrke, C
    Hermetter, A
    Russwurm, S
    Daniel, V
    Hack, V
    Metz, J
    [J]. FEBS LETTERS, 1997, 405 (01): : 55 - 59
  • [47] THE SPHINGOMYELIN PATHWAY IN TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1 SIGNALING
    KOLESNICK, R
    GOLDE, DW
    [J]. CELL, 1994, 77 (03) : 325 - 328
  • [48] Tumor necrosis factor-α stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase
    Lawler, JF
    Yin, M
    Diehl, AM
    Roberts, E
    Chatterjee, S
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (09) : 5053 - 5059
  • [49] CLEAVAGE OF POLY(ADP-RIBOSE) POLYMERASE BY A PROTEINASE WITH PROPERTIES LIKE ICE
    LAZEBNIK, YA
    KAUFMANN, SH
    DESNOYERS, S
    POIRIER, GG
    EARNSHAW, WC
    [J]. NATURE, 1994, 371 (6495) : 346 - 347
  • [50] LINARDIC CM, 1994, J BIOL CHEM, V269, P23530