Pharmacological Preconditioning by Adenosine A2a Receptor Stimulation: Features of the Protected Liver Cell Phenotype

Abstract

Ischemic preconditioning (IP) of the liver by a brief interruption of the blood flow protects the damage induced by a subsequent ischemia/reperfusion (I/R) preventing parenchymal and nonparenchymal liver cell damage. The discovery of IP has shown the existence of intrinsic systems of cytoprotection whose activation can stave off the progression of irreversible tissue damage. Deciphering the molecular mediators that underlie the cytoprotective effects of preconditioning can pave the way to important therapeutic possibilities. Pharmacological activation of critical mediators of IP would be expected to emulate or even to intensify its salubrious effects. In vitro and in vivo studies have demonstrated the role of the adenosine A2a receptor (A2aR) as a trigger of liver IP. This review will provide insight into the phenotypic changes that underline the resistance to death of liver cells preconditioned by pharmacological activation of A2aR and their implications to develop innovative strategies against liver IR damage.

Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver

“…Therefore, modulation of mitochondria has emerged as a critical survival strategy for the prevention of I/R injury. IPC-triggered signal transduction appears to directly preserve several cell functions including intracellular energy state, pH, and redox system [2,3,14,17,24]. Our data show that PC (both ischemic and pharmacological) was capable to decrease the plasma activities of ALT, AST, and LDH, indicating a clear hepatoprotective effect against warm I/R injury.…”

“…Accumulated evidence suggests that A1R play a role in the protection from I/R injury in several organs such as heart, brain, and lung [12][13][14][26][27][28][29][30][31][32][33][34][35][36][37] through mechanisms that remain to be defined. The present study suggests that A1R activation prevents I/R injury through the control of OXPHOS efficiency.…”

“…Furthermore, IPC decreases liver injury after both warm and cold I/R [2,4,9,10]. Several mechanisms have been proposed for protection by IPC, including activation of adenosine receptors [11][12][13][14], increased nitric oxide production [15], activation of protein kinase C [16], up-regulation of heat shock proteins, and increased antioxidant capacity [17,18]. Probably, the process better established to be associated with decrease tolerance to I/R injury is the inability to restore energetic balance following I/R [1,19,20].…”

“…Accordingly, IPC can prevent I/R-induced mitochondrial dysfunction suggesting that PC protects the integrity of mitochondrial oxidative phosphorylation (OXPHOS) and increases the resistance to the induction of the mitochondrial permeability transition [21][22][23]. The precise mechanism of PC-induced hepatoprotection is unknown, but it is likely to be a receptor-mediated process, related with preservation of energy metabolism [2,3,14,17,24]. However, little is known about the coupling of extracellular signals with intracellular adaptive mechanisms involved in preconditioning.…”

“…Albeit it is expectable that mitochondrial function should be a key target of A1R-mediated effects, the link between both is still to be established but seems likely in view of the described ability of A1R to preserve mitochondrial membrane potential and the sensitivity to pro-oxidant stressors in the setting of hepatic I/R [14,35,36]. The present study was designed to critically evaluate the role of A1R and to identify mitochondrial downstream targets involved in hepatic PC protection activated by A1R.…”