Department of Neurology, Xuzhou Medical College Affiliated Hospital, Xuzhou, Jiangsu Province, China.
J Neurochem. 2012 Jan;120(1):70-7. doi: 10.1111/j.1471-4159.2011.07526.x. Epub 2011 Nov 18.
Caspase-dependent apoptosis is considered one of the most important cell death pathways. When the apoptotic process is blocked, a form of programmed necrosis called necroptosis occurs. Apoptosis and necroptosis may share some regulatory mechanisms. Recent studies indicated that receptor interacting protein 1 (RIP1), an Hsp90-associated kinase, is an important regulatory switch between apoptosis and necroptosis. In this study, we showed that oxygen-glucose deprivation (OGD) combined with a caspase inhibitor zVAD (OGD/zVAD)-induced RIP1 protein expression in a time-dependent manner. We found that geldanamycin (GA), a benzoquinone ansamycin, protected against neuronal injury induced by OGD/zVAD treatment in cultured primary neurons. More importantly, GA decreased RIP1 protein level in a time- and concentration-dependent manner. In this study, we found that GA also decreased the Hsp90 protein level, which caused instability of RIP1 protein, resulting in decreased RIP1 protein level but not RIP1 mRNA level after GA treatment. We concluded that the GA-mediated protection against OGD/zVAD-induced neuronal injury was associated with enhanced RIP1 protein instability by decreasing Hsp90 protein level. GA and its derivatives may be promising for the prevention of neuronal injury during ischemic injury.
Caspase-依赖性细胞凋亡被认为是最重要的细胞死亡途径之一。当凋亡过程受阻时，会发生一种称为坏死性细胞凋亡的程序性坏死形式。凋亡和坏死性细胞凋亡可能共享一些调节机制。最近的研究表明，受体相互作用蛋白 1（RIP1）是一种与热休克蛋白 90 相关的激酶，是凋亡和坏死性细胞凋亡之间的重要调节开关。在这项研究中，我们表明，氧葡萄糖剥夺（OGD）联合半胱天冬酶抑制剂 zVAD（OGD/zVAD）以时间依赖性方式诱导 RIP1 蛋白表达。我们发现，格尔德霉素（GA），一种苯醌 ansamycin，可防止培养的原代神经元中 OGD/zVAD 处理引起的神经元损伤。更重要的是，GA 以时间和浓度依赖性方式降低 RIP1 蛋白水平。在这项研究中，我们发现 GA 还降低了热休克蛋白 90 蛋白水平，导致 RIP1 蛋白不稳定，导致 GA 处理后 RIP1 蛋白水平降低，但 RIP1 mRNA 水平不变。我们得出结论，GA 通过降低热休克蛋白 90 蛋白水平来增强 RIP1 蛋白的不稳定性，从而介导对 OGD/zVAD 诱导的神经元损伤的保护作用。GA 及其衍生物可能有望预防缺血性损伤期间的神经元损伤。
