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

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 Ca(2+) 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.

Protective effects of endothelin receptor A and B inhibitors against doxorubicin-induced cardiomyopathy

“…Co-application of the ERAs normalized (bosentan, BQ788) or even increased (sitaxentan) the dox-mediated reduction of Ant1 protein which could be an essential part of the amelioration of the cardiac performance by ERA co-medication. A kinase which also modulates the PTP is Akt1 [50]. To date a decreased cardiac phosphorylation of the kinase Akt1 (pAkt1) by dox application was not described in the literature but it is known that substances like adiponectin or tanshinone IIA, which reduce the dox mediated cardiac injury, increase the pAkt1 content in the myocardium [51,52].…”

The Molecular and Physiological Effects of Protein-Derived Polyamines in the Intestine

“…The impact of polyamines on MPTP was shown to be relevant in models of ischeamia/reperfusion injury. Upon ischemia/reperfusion injury of heart muscles, ODC1 was found to be upregulated, thereby elevating the intracellular polyamine content [88]. This was shown to have a positive effect on survival and recovery [88].…”

Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission

“…In cardiac cells, this ODC1 induction is caused by the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2; also known as P42/P44 MAPK), and P13K/Akt pathways (Pernet et al, 2007; Zhang et al, 2014b). ODC1 activation by ERK1/2 is also dependent on Ca 2+ -mediated activation of calpain (Moldoveanu et al, 2002).…”