The sphingomyelin-ceramide signaling pathway is involved in oxidized low density lipoprotein-induced cell proliferation
The sphingomyelin-ceramide signaling pathway is involved in oxidized low density lipoprotein-induced cell proliferation
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DOI：
10.1074/jbc.271.32.19251
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发表时间：
1996-08-09
影响因子：
4.8
通讯作者：
Salvayre, R
中科院分区：
文献类型：
--
作者：
Auge, N;Andrieu, N;Salvayre, R
动脉粥样硬化的发展被认为涉及平滑肌细胞（SMC）的增殖。我们的实验室先前证明，牛主动脉SMC的生长受到轻度氧化的低密度脂蛋白（oxLDL）的刺激，并且oxLDL的促有丝分裂作用大于天然LDL诱导的促有丝分裂作用（AugB，N.，Pieraggi，M. T.，Thiers，J. C.，Negre-Salvayre，A.，和Salvayre R.（1995）Biochem.J.309，1015-1020）。由于脂质介质神经酰胺已被描述为是增殖的，目前的工作旨在研究所谓的鞘磷脂神经酰胺途径在oxLDL诱导的信号转导级联中的潜在参与。SMC与UV-氧化LDL孵育诱导鞘磷脂水解（32%），在60分钟达到峰值，并伴随着细胞内神经酰胺水平的增加。氧化型LDL对鞘磷脂代谢的影响与其促有丝分裂作用具有相同的LDL剂量依赖性。与外源性磷脂酶A2、C或D相反，外源性细菌鞘磷脂酶诱导鞘磷脂水解和神经酰胺生成，并刺激细胞生长。通过将细胞与细胞渗透性神经酰胺、N-乙酰基-和N-己酰鞘氨醇一起孵育来再现这种促有丝分裂作用。总之，这些数据首次强烈表明，鞘磷脂-神经酰胺通路的激活可能在oxLDL诱导的SMC增殖和动脉粥样硬化形成中发挥关键作用。
Development of atherosclerosis is believed to involve proliferation of smooth muscle cells (SMC). Our laboratory previously demonstrated that the growth of bovine aortic SMC was stimulated by mildly oxidized low density lipoproteins (oxLDL) and that the mitogenic effect of oxLDL was greater than that induced by native LDL (AugB, N., Pieraggi, M. T., Thiers, J. C., Negre-Salvayre, A., and Salvayre R. (1995) Biochem. J. 309, 1015-1020). Since the lipid mediator ceramide has been described to be proliferative, the present work aimed at studying the potential involvement of the so-called sphingomyelin ceramide pathway in the Signal transduction cascade induced by oxLDL. Incubation of SMC with UV-oxidized LDL induced sphingomyelin hydrolysis (32%), which peaked at 60 min and was accompanied by a concomitant increase of intracellular ceramide level. The effect of oxidized LDL on sphingomyelin turnover exhibited the same LDL dose dependence as their mitogenic effect, Exogenous bacterial sphingomyelinase induced sphingomyelin hydrolysis and ceramide generation and also stimulated cell growth, in contrast to exogenous phospholipases A2, C, or D. This mitogenic effect was reproduced by incubating the cells with the cell-permeant ceramides, N-acetyl- and N-hexanoylsphingosines. Altogether, these data strongly suggest for the first time that activation of the sphingomyelin-ceramide pathway may play a pivotal role in the oxLDL-induced SMC proliferation and atherogenesis.