Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction: A novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis
Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction: A novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis
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DOI：
10.1016/j.yexcr.2006.12.001
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发表时间：
2007-02-15
影响因子：
3.7
通讯作者：
Goldkorn, Tzipora
中科院分区：
文献类型：
--
作者：
Castillo, S. Sianna;Levy, Michal;Goldkorn, Tzipora
活性氮物质（RNS）与炎症性肺病（如哮喘和慢性阻塞性肺病）的病理生理学有关。RNS引起肺细胞损伤的分子机制和信号转导途径尚不清楚。在目前的研究中，我们观察到一种新的抗凋亡反应，一氧化氮（NO）暴露（通过NO供体3-吗啉-syndnonimine（SIN 1）或papa-NONOate）的人气道上皮（HAE）细胞。没有暴露通过NO供体通过神经酰胺合成酶增加细胞神经酰胺水平，但没有引发凋亡反应。相反，暴露于NO供体促进酸性鞘磷脂酶（aSMase）和caspase-3之间的蛋白质-蛋白质相互作用的增加，aSMase螯合caspase-3并阻止其裂解。相反，当aSMase在HAE细胞中沉默或在小鼠中敲除时，观察到裂解的半胱天冬酶-3增加。这种升高的半胱天冬酶-3裂解在HAE细胞的NO暴露（通过SIN 1或papa-NONOate）后进一步增强，并且可以通过神经酰胺合酶抑制剂来防止。这些结果证明了NO调节细胞凋亡的新机制，其中通过NO供体暴露于NO的HAE细胞通过神经酰胺合酶诱导神经酰胺产生。然而，这种神经酰胺诱导不会导致细胞凋亡，除非aSMase被敲低，从而释放半胱天冬酶-3，激活并执行细胞凋亡。(c)2006年爱思唯尔公司All rights reserved.
Reactive nitrogen species (RNS) are implicated in the pathophysiology of inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease. The molecular mechanisms and signaling events involved in lung cell injury by RNS are still poorly understood. In the current study, we observe a novel anti-apoptotic response to nitric oxide (NO) exposure (via the NO donors 3-morpholine-syndnonimine (SIN1) or papa-NONOate) of human airway epithelial (HAE) cells. No exposure via the NO donors increased cellular ceramide levels via ceramide synthase but did not trigger an apoptotic response. Rather, exposure to the No donors promoted an increase in the protein-protein interaction between acidic sphingomyelinase (aSMase) and caspase-3, with aSMase sequestering caspase-3 and preventing its cleavage. In contrast, when aSMase was silenced in HAE cells or was knocked out in mice, an increase in cleaved caspase-3 was observed, This elevated caspase-3 cleavage was further augmented upon NO exposure (via SIN1 or papa-NONOate) of HAE cells and could be prevented by an inhibitor to ceramide synthase. These results demonstrate a novel mechanism of NO modulation of apoptosis, in which HAE cells exposed to NO via an NO donor induces ceramide generation via ceramide synthase. However, this ceramide induction does not lead to apoptosis unless aSMase is knocked down, allowing the release of caspase-3, its activation and execution of apoptosis. (c) 2006 Elsevier Inc. All rights reserved.