Pan Li-Long, Liu Xin-Hua, Jia Yao-Ling, Wu Dan, Xiong Qing-Hui, Gong Qi-Hai, Wang Yang, Zhu Yi-Zhun
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
Biochim Biophys Acta. 2013 Apr;1830(4):2861-71. doi: 10.1016/j.bbagen.2013.01.008. Epub 2013 Jan 14.
Heme oxygenase-1 (HO-1) has potential anti-apoptotic properties. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2- ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)] was synthesized by joining danshensu and cysteine through an appropriate linker. This study investigated if the cytoprotective properties of DSC involved the induction of HO-1.
We evaluated the cytoprotective effects of DSC on H2O2-induced cell damage, apoptosis, intracellular and mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm) loss, and apoptosis-related proteins expression and its underlying mechanisms.
DSC concentration-dependently attenuated cell death, lactate dehydrogenase release, intracellular and mitochondrial ROS production, and ΔΨm collapse, modulated apoptosis-related proteins (Bcl-2, Bax, caspase-3, p53, and cleaved PARP) expression, and inhibited phosphorylation of extracellular signal-regulated kinase 1/2 in SH-SY5Y cells induced by H2O2. In addition, DSC concentration-dependently induced HO-1 expression associated with nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf-2), while the effect of DSC was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Furthermore, the protective effect of DSC on H2O2-induced cell death was abolished by HO-1 inhibitor ZnPP, but was mimicked by carbon monoxide-releasing moiety CORM-3 or HO-1 by-product bilirubin. Finally, DSC inhibited H2O2-induced changes of Bcl-2, Bax, and caspase-3 expression, and all of these effects were reversed by HO-1 silencing.
Induction of HO-1 may be, at least in part, responsible for the anti-apoptotic property of DSC, an effect that involved the activation of PI3K/Akt/Nrf-2 axis.
DSC might have the potential for beneficial therapeutic interventions for neurodegenerative diseases.
血红素加氧酶-1（HO-1）具有潜在的抗凋亡特性。一种新型化合物[4-(2-乙酰氧基-3-((R)-3-(苄硫基)-1-甲氧基-1-氧代丙烷-2-基氨基)-3-氧代丙基)-1,2-亚苯基二乙酸酯（DSC）]通过合适的连接子将丹参素和半胱氨酸连接而成。本研究调查了DSC的细胞保护特性是否涉及HO-1的诱导。
我们评估了DSC对H2O2诱导的细胞损伤、凋亡、细胞内和线粒体活性氧（ROS）产生、线粒体膜电位（ΔΨm）丧失、凋亡相关蛋白表达及其潜在机制的细胞保护作用。
DSC以浓度依赖的方式减轻细胞死亡、乳酸脱氢酶释放、细胞内和线粒体ROS产生以及ΔΨm崩溃，调节凋亡相关蛋白（Bcl-2、Bax、caspase-3、p53和裂解的PARP）表达，并抑制H2O2诱导的SH-SY5Y细胞中细胞外信号调节激酶1/2的磷酸化。此外，DSC以浓度依赖的方式诱导与核因子红细胞2相关因子2（Nrf-2）核转位相关的HO-1表达，而DSC的作用被磷酸肌醇3-激酶（PI3K）抑制剂LY294002抑制。此外，HO-1抑制剂ZnPP消除了DSC对H2O2诱导的细胞死亡的保护作用，但一氧化碳释放分子CORM-3或HO-1副产物胆红素模拟了该作用。最后，DSC抑制H2O2诱导的Bcl-2、Bax和caspase-3表达变化，而HO-1沉默逆转了所有这些作用。
HO-1的诱导可能至少部分负责DSC的抗凋亡特性，这一作用涉及PI3K/Akt/Nrf-2轴的激活。
DSC可能对神经退行性疾病具有有益治疗干预的潜力。
