Prothymosin alpha protects cardiomyocytes against ischemia-induced apoptosis via preservation of Akt activation
Prothymosin alpha protects cardiomyocytes against ischemia-induced apoptosis via preservation of Akt activation
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DOI：
10.1007/s10495-013-0876-9
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发表时间：
2013-10-01
期刊：
影响因子：
7.2
通讯作者：
Esposito, Giovanni
中科院分区：
文献类型：
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作者：
Cannavo, Alessandro;Rengo, Giuseppe;Esposito, Giovanni
人胸腺素原α(PTα)基因编码12.5 kDa的高度酸性核蛋白，广泛表达于包括心脏在内的哺乳动物组织中，更重要的是，在血清中也可检测到。在细胞凋亡或坏死过程中，PTα改变其核定位，发挥重要的细胞保护作用。由于PTα在心脏中的作用从未被评估过，本研究的目的是探讨PTα在心肌细胞缺血损伤中的作用。我们的数据显示，心肌梗死后7周，PTα在血清和心肌组织中的表达水平均显著升高，值得注意的是，我们观察到心肌梗死后PTα从胞核移位到细胞质和质膜。此外，在心肌细胞的体外实验证实，在模拟缺血(SI)6h后，PTα蛋白水平比正常氧细胞上调。重要的是，在SI期间用重组PTα(RPTα)处理心肌细胞可显著降低细胞的凋亡反应，并显著增加细胞存活率。此外，这些作用还伴随着显著地保存了抗细胞凋亡的丝氨酸-苏氨酸激酶Akt的激活水平。与我们的体外观察一致，RPTα处理的MI小鼠在24小时显示出与MI对照组相比显著的缩小梗塞面积，并且在分子水平上，PTα处理诱导Akt的激活。本研究首次证明PTα通过Akt依赖机制提供对缺血损伤的心脏保护作用。
The human prothymosin alpha (PT alpha) gene encodes a 12.5 kDa highly acidic nuclear protein that is widely expressed in mammalian tissues including the heart and importantly, is detectable also in blood serum. During apoptosis or necrosis, PT alpha changes its nuclear localization and is able to exert an important cytoprotective effect. Since the role of PT alpha in the heart has never been evaluated, the aim of the present study was to investigate the effects of PT alpha on cardiomyocytes during ischemic injury. Our data show that seven after myocardial infarction (MI), PT alpha expression levels are significantly increased both in blood serum and in cardiac tissue, and notably we observe that PT alpha translocates from the nuclei to cytoplasm and plasma membrane of cardiomyocytes following MI. Furthermore, in vitro experiments in cardiomyocytes, confirm that after 6 h of simulated ischemia (SI), PT alpha protein levels are upregulated compared to normoxic cells. Importantly, treatment of cardiomyocytes with a recombinant PT alpha (rPT alpha), during SI results in a significant decrease in the apoptotic response and in a robust increase in cell survival. Moreover, these effects are accompanied to a significant preservation of the activated levels of the anti-apoptotic serine-threonine kinase Akt. Consistent with our in vitro observation, rPT alpha-treated MI mice exhibit a strong reduction in infarct size at 24 h, compared to the MI control group and at the molecular level, PT alpha treatment induces activation of Akt. The present study provides for the first time the demonstration that PT alpha offers cardioprotection against ischemic injury by an Akt-dependent mechanism.