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Akt and Erk1/2 activate the ornithine decarboxylase/polyamine system in cardioprotective ischemic preconditioning in rats: the role of mitochondrial permeability transition pores

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Abstract

Ornithine decarboxylase (ODC) is the first rate-limiting enzyme in polyamine biosynthesis, which is essential for cell survival. We hypothesized that the ODC/polyamine system is involved in ischemic preconditioning (IPC)-mediated cardioprotection through the activation of Erk1/2 and Akt and through the inhibition of the mitochondrial permeability transition (mPT). Isolated rat hearts were subjected to 40 min of ischemia either with or without IPC (3 cycles of 5-min global ischemia), and ODC protein expression, polyamine content, and Akt and Erk1/2 phosphorylation were evaluated after 30 min of reperfusion. IPC significantly upregulated the ODC/polyamine pathway, promoted Erk1/2 and Akt phosphorylation, and reduced the infarct size and heart dysfunction after reperfusion. An inhibitor of ODC, α-difluoromethylornithine (DFMO), abolished the IPC-induced cardioprotection. Moreover, the inhibition of the IPC-induced activation of Erk1/2 and Akt using PD98059 or wortmannin downregulated the ODC/polyamine system. In separate studies, the Ca2+ load required to open the mPT pore was significantly lower in DFMO-treated cardiac mitochondria than in mitochondria from IPC hearts. Furthermore, spermine or spermidine significantly inhibited the mPT induced by CaCl2. These results suggest that IPC upregulates the ODC/polyamine system and mediates preconditioning cardioprotection, which may depend on the phosphorylation/activation of Erk1/2 and Akt and on the inhibition of the mPT during reperfusion.

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (81170178, 81170289, 81170218, 81100163, and 81100170).

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Authors and Affiliations

  1. Department of Pathophysiology, Harbin Medical University, 150086, Harbin, China

    Hao Zhang, Weihua Zhang, Lina Wang, Hong Li, Li Zhang, Fanghao Lu, Shuzhi Bai, Changqing Xu & Yajun Zhao

  2. Department of Pathology, Heilongjiang Electric Power Hospital, 150090, Harbin, China

    Guo Xue

  3. Department of Pathophysiology, Qiqihar Medical University, 161042, Qiqihar, China

    Yan Lin

  4. Department of Cardiology, The First Clinical Hospital of Harbin Medical University, 150001, Harbin, China

    Yu Lou

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  1. Hao Zhang
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Correspondence to Yajun Zhao.

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Zhang, H., Xue, G., Zhang, W. et al. Akt and Erk1/2 activate the ornithine decarboxylase/polyamine system in cardioprotective ischemic preconditioning in rats: the role of mitochondrial permeability transition pores. Mol Cell Biochem 390, 133–142 (2014). https://doi.org/10.1007/s11010-014-1964-z

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