AMP-Activated Protein Kinase as a Target for Preconditioning in Transplantation Medicine

We have read with interest the recent review by Bouma et al. (1). They reviewed the role of adenosine monophosphate-activated kinase (AMPK) in liver preservation against ischemia-reperfusion (I/R) injury. The authors summarized available literature regarding the protective signaling pathways activated by I/R and preconditioning and how they can be activated pharmacologically. Finally, they concluded that AMPK activation before or during organ preservation might be a promising pharmacologic approach to limit organ injury and maintain graft quality before transplantation. This review refers to previous results from our group but lacks some recent results that we find of great interest and that could perfectly complete the review. Bouma et al. (1) observed that preconditioning can activate AMPK through an increase in adenosine monophosphate levels (2). AMPK can then act on its downstream targets and lead the liver toward an energy-conserving state (3). One of the main AMPK targets is endothelial nitric oxide (NO) synthase, which produces NO, a well-known vasodilator molecule that protects the liver from endothelial cell dysfunction after cold preservation (4). It is well established that NO production in the liver can protect it from I/R injury and cold preservation (5, 6), and thus, AMPK activation or NO production in the liver could reduce liver injury after transplantation and so, improve its outcome. In this review, the authors focus on different pharmacologic pretreatments that can activate AMPK and thus improve organ functioning after cold storage. In our opinion, if AMPK should be activated during cold storage, it would be of interest to assess this through the preservation solution. Previous results from our group revealed that the new preservation solution, Institute Georges Lopez solution (IGL)-1, reduces liver injury after I/R through and increases NO production (7, 8). Moreover, this NO increase is a consequence of constitutive NO synthase activation (8). Livers preserved in this solution show decreased transaminase levels in liver effluents, improved vascular resistance, and ameliorated liver function (8). Furthermore, we also observed that most preservation solutions such as University of Wisconsin, which is the most widely used in transplantation, are serum-free preservation solutions (9). To that end, we investigated the effect of adding different biologic agents such as trophic factors such as insulin-like growth factor (IGF)-1 to the preservation solution. Addition of IGF-1 to IGL-1 increased fatty liver graft preservation, thus reducing the risk of steatotic livers from suffering cold I/R injury (10). The mechanisms responsible for this were closely associated with the exacerbation of NO through AKT activation. In addition, the release of proinflammatory cytokines such as tumor necrosis factor-α was reduced (10). From our studies, we believe that synergism between pharmacologic agents and biologic agents are of high interest in liver preservation. Seeing this, combined administration of a biologic agent such as IGF-1 and other hormones and a pharmacologic activator of AMPK such as aminoimidazole-4-carboxamide ribonucleoside, a well-known activator of AMPK (6), in a preservation solution, such as IGL-1, could show a synergic effect on NO production in the liver that could be translated in a drastically ameliorated protection of the liver against I/R injury and cold preservation. What it is clear is that AMPK, as Bouma et al. (1) perfectly defined in their review, is the key target and clear regulator in all this processes. This leads us to wonder if both IGL-1 solution and IGF-1 addition to the solution modulate AMPK signaling in the liver during cold preservation, this could be the object of future studies of our group. Susagna Padrissa-Altés Mohamed Amine Zaoualí Joan Roselló-Catafau 1Experimental Hepatic Ischemia-Reperfusion Unit Institut d'Investigacions Biomèdiques de Barcelona (IIBB) Consejo Superior de Investigaciones Científicas Barcelona, Spain 2Unitat de Transplantament de Fetge i Viabilitat de l'Empelt Institut d'Investigacions Biomèdiques August Pi i Sunyer(IDIBAPS) Barcelona, Spain 3Centro de Investigaciones Biomédicas Esther Koplowitz CIBER-ehd Instituto de Salud Carlos III Barcelona, Spain