Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species
Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species
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DOI：
10.1002/hep.22285
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发表时间：
2008-06-01
期刊：
影响因子：
13.5
通讯作者：
Shah, Vijay H.
中科院分区：
文献类型：
--
作者：
Langer, Daniel A.;Das, Amitava;Shah, Vijay H.
肝星状细胞（hepatic stellate cells，HSC）通过胶原沉积、血管收缩和调节肝窦结构等多种机制参与门静脉高压的发生。在正常生理条件下，内皮型一氧化氮（NO）脱氢酶衍生的NO对HSC产生旁分泌作用;然而，在肝硬化中，NO的产生与伴随的HSC活化和窦状结构的变化相关，这些事件显著促进门静脉高压的发展。这些概念，结合最近的证据表明，诱导HSC选择性凋亡可能是一个有用的目标，用于治疗慢性肝病，使我们检查是否NO可能通过凋亡进一步限制HSC功能。事实上，NO供体和内皮NO合酶过表达促进HSC凋亡途径。NO通过线粒体膜去极化和非半胱天冬酶依赖性途径诱导HSC死亡。此外，NO诱导的HSC凋亡并没有发生通过可溶性鸟苷酸环化酶或蛋白质硝化的经典途径，而是通过产生超氧化物和羟基自由基中间体。胆管结扎后的大鼠肝星状细胞对NO诱导的凋亡更敏感。这些数据表明，NO通过涉及线粒体的信号传导机制促进HSC凋亡，由活性氧介导，并且独立于半胱天冬酶激活而发生。总结：我们推测，一氧化氮依赖的肝星状细胞凋亡可能维持窦内稳态，并可能代表了一个额外的有益的影响，NO供体治疗门静脉高压症。
Hepatic stellate cells (HSCs) contribute to portal hypertension through multiple mechanisms that include collagen deposition, vasoconstriction, and regulation of sinusoidal structure. Under normal physiologic conditions, endothelial nitric oxide (NO) synthase-derived NO exerts paracrine effects on HSCs; however, in cirrhosis, NO generation is impaired in association with concomitant HSC activation and changes in sinusoidal structure, events that contribute significantly to the development of portal hypertension. These concepts, in combination with recent evidence that induction of HSC-selective apoptosis may represent a useful target for treatment of chronic liver disease, led us to examine ifNO may further limit HSC function through apoptosis. Indeed, both NO donors and endothelial NO synthase overexpression promoted HSC apoptotic pathways. HSC death conferred by NO occurred through mitochondrial membrane depolarization and through a caspase-independent pathway. Furthermore, NO-induced apoptosis of HSC did not occur through the canonical pathways of soluble guanylate cyclase or protein nitration, but rather through the generation of superoxide and hydroxyl radical intermediates. Lastly, HSC isolated from rats after bile duct ligation were more susceptible to NO-induced apoptosis. These data indicate that NO promotes HSC apoptosis through a signaling mechanism that involves mitochondria, is mediated by reactive oxygen species, and occurs independent of caspase activation. Conclusion: We postulate that NO-dependent apoptosis of HSCs may maintain sinusoidal homeostasis, and may represent an additional beneficial effect of NO donors for therapy of portal hypertension.