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首页> 外文期刊>American Journal of Physiology >Neutral sphingomyelinase inhibitor scyphostatin prevents and ceramide mimics mechanotransduction in vascular endothelium.
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Neutral sphingomyelinase inhibitor scyphostatin prevents and ceramide mimics mechanotransduction in vascular endothelium.

机译：中性鞘磷脂酶抑制剂鞘磷脂抑制素可防止和神经酰胺模拟血管内皮的机械传导。

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Recently, we showed that neutral sphingomyelinase (N-SMase) is concentrated at the endothelial cell surface in caveolae and is activated to produce ceramide in an acute and transient manner by increase in flow rate and pressure in rat lung vasculature (Czarny M, Liu J, Oh P, and Schnitzer JE, J Biol Chem 278: 4424-4430, 2003). Here, we report further on our investigations of this new acute mechanotransduction pathway. We employed three experimental models to explore the role of N-SMase and ceramides in mechanosignaling: 1) a cell-free, in vitro model using isolated luminal plasma membranes of rat lung endothelium; 2) a fluid shear stress model using monolayers of intact bovine aorta endothelial cell in culture; and 3) an in situ model using controlled perfusion of the rat lung vasculature. Scyphostatin, which specifically inhibited N-SMase but not acid SMase activity, prevented mechanoactivation of N-SMase as well as downstream tyrosine and mitogen-activated protein kinases. Cell-permeable ceramide analogs (N-acetylsphingosine, C2-ceramide, and N-hexanoylsphingosine, C6-ceramide) but not the inactive dihydroderivatives D2-ceramide and D6-ceramide (N-acetylsphinganine and N-hexanoylsphinganine, respectively) mimic rapid mechano-induced tyrosine phosphorylation of cell surface proteins as well as mechanoactivation of Src-like kinases and the extracellular regulated kinase pathway. The responses common to ceramide and mechanical stress were inhibited by genistein, herbamycin A, and PP2, but not PP3, which suggests an obligate role of Src-like kinases in ceramide-mediated mechanotransduction. Ceramides also induced serine/threonine phosphorylation to activate the Akt/endothelial nitric oxide synthase pathway. Thus N-SMase at the plasma membrane in caveolae may be an upstream initiating mechanosensor, which acutely triggers mechanotransduction by generation of the lipid second messenger ceramide.
机译：最近，我们发现中性鞘磷脂酶（N-SMase）集中在小窝的内皮细胞表面，并通过增加大鼠肺血管的流速和压力而被激活以急性和短暂的方式产生神经酰胺（Czarny M，Liu J ，Oh P，和Schnitzer JE，J Biol Chem 278：4424-4430，2003）。在这里，我们将进一步报告对这种新的急性机械转导途径的研究。我们采用了三种实验模型来探索N-SMase和神经酰胺在机械信号转导中的作用：1）使用大鼠肺内皮的分离的腔质膜的无细胞体外模型; 2）使用培养的完整牛主动脉内皮细胞单层的流体剪切应力模型; 3）使用大鼠肺血管的受控灌注的原位模型。胱抑素可以特异性抑制N-SMase的活性，但不能抑制酸性SMase的活性，因此可以阻止N-SMase的机械活化以及下游的酪氨酸和丝裂原活化的蛋白激酶。细胞可渗透的神经酰胺类似物（N-乙酰基鞘氨醇，C2-神经酰胺和N-己酰基鞘氨醇，C6-神经酰胺），而非失活的二氢衍生物D2-神经酰胺和D6-神经酰胺（分别为N-乙酰鞘氨醇和N-己基鞘氨醇）模拟快速机械机械诱导细胞表面蛋白的酪氨酸磷酸化以及Src样激酶的机械活化和细胞外调节的激酶途径。金雀异黄素，草胺素A和PP2抑制了对神经酰胺和机械应力的共同反应，但对PP3没有抑制作用，这表明Src样激酶在神经酰胺介导的机械转导中起着重要作用。神经酰胺还诱导丝氨酸/苏氨酸磷酸化，从而激活Akt /内皮一氧化氮合酶途径。因此，小窝质膜上的N-SMase可能是上游启动机械传感器，它通过产生脂质第二信使神经酰胺而急性触发机械转导。

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