Prothymosin alpha protects cardiomyocytes against ischemia-induced apoptosis via preservation of Akt activation

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.