Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways
Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways
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DOI：
10.1007/s10495-006-9037-8
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发表时间：
2006-09-01
期刊：
影响因子：
7.2
通讯作者：
Zhao, Zhi-Qing
中科院分区：
文献类型：
--
作者：
Sun, He-Ying;Wang, Ning-Ping;Zhao, Zhi-Qing
氧气供应的一系列间歇性中断（即，后处理（Postconditioning，Postcon）减少氧化剂诱导的心肌细胞损失。本研究验证了Postcon通过丝裂原活化蛋白激酶途径预防心肌细胞凋亡的假设。将原代培养的新生大鼠心肌细胞暴露于3 h缺氧，随后6 h复氧。心肌细胞后处理3个周期，每个周期5分钟的复氧和5分钟的缺氧后，长时间缺氧。相对于单纯缺氧，复氧刺激JNKs和p38激酶的表达，对应于JNKs（磷酸-c-Jun）和p38（磷酸-ATF 2）活性的增加。再给氧后，心肌细胞裂解液中TNF α水平、胞浆caspase-8、-3活性、Bax表达及凋亡细胞数增加，Bcl-2表达减少。与在复氧早期通过光泽精增强的化学发光检测到的超氧阴离子产生的衰减一致，用Postcon处理心肌细胞进一步降低了JNKs和p38激酶的表达和活性、TNF α的水平、凋亡细胞的频率和Bax的表达。然而，Postcon对这些变化的抑制作用时，其应用程序被延迟5分钟后开始复氧失去。在复氧开始时向心肌细胞中加入JNK/p38刺激剂茴香霉素消除了Postcon的保护作用。这些数据表明：1）缺氧/复氧与JNK和p38激酶的表达和激活、TNF α的释放、caspase的激活以及促凋亡/抗凋亡蛋白失衡的增加相结合，诱发心肌细胞凋亡; 2）Postcon可能通过抑制JNK/p-38信号通路和减少TNF α释放和caspase表达来减弱心肌细胞凋亡。
A sequence of intermittent interruptions of oxygen supply (i.e., postconditioning, Postcon) at reoxygenation reduces oxidant-induced cardiomyocyte loss. This study tested the hypothesis that prevention of cardiomyocyte apoptosis by Postcon is mediated by mitogen-activated protein kinases pathways. Primary cultured neonatal rat cardiomyocytes were exposed to 3 h hypoxia followed by 6 h of reoxygenation. Cardiomyocytes were postconditioned by three cycles each of 5 min reoxygenation and 5 min hypoxia after prolonged hypoxia. Relative to hypoxia alone, reoxygenation stimulated expression of JNKs and p38 kinases, corresponding to increased activity of JNKs (phospho-c-Jun) and p38 (phospho-ATF2). The level of TNF alpha in cell lysates, activity of cytosolic caspases-8, -3, expression of Bax and the number of apoptotic cardiomyocytes were increased while expression of Bcl-2 was decreased with reoxygenation. Consistent with an attenuation in generation of superoxide anions detected by lucigenin-enhanced chemiluminescence at early period of reoxygenation, treatment of cardiomyocytes with Postcon further reduced expression and activity of JNKs and p38 kinases, level of TNF alpha, the frequency of apoptotic cells and expression of Bax. However, the inhibitory effects of Postcon on these changes were lost when its application was delayed by 5 min after the start of reoxygenation. Addition of a JNK/p38 stimulator, anisomycin into cardiomyocytes at the beginning of reoxygenation eliminated protection by Postcon. These data suggest that 1) hypoxia/reoxygenation elicits cardiomyocyte apoptosis in conjunction with expression and activation of JNK and p38 kinases, release of TNF alpha, activation of caspases, and an increase in imbalance of pro-/anti-apoptotic proteins; 2) Postcon attenuates cardiomyocyte apoptosis, potentially mediated by inhibiting JNKs/p-38 signaling pathways and reducing TNF alpha release and caspase expression.