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

Abstract

Although adenosine A 1 receptors (A1R) have been associated to ischemic preconditioning (IPC), direct evidence for their ability to preserve mitochondrial function upon hepatic preconditioning is still missing and could represent a novel strategy to boost the quality of liver transplants. We tested if the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prevented IPC in the liver and if the A1R agonist 2-chloro-N 6 -cyclopentyladenosine (CCPA) might afford a pharmacological preconditioning. Livers underwent a 120 min of 70% warm ischemia and 16 h of reperfusion (I/R), and the IPC group underwent a 5-min ischemic episode followed by a 10-min period of reperfusion before I/R. DPCPX or CCPA was administered intraperitoneally 2 h before IPC or I/R. The control of mitochondrial function emerged as the central element affected by IPC and controlled by endogenous A1R activation. Thus, livers from IPC-or CCPA-treated rats displayed an improved oxidative phosphorylation with higher state 3 respiratory rate, higher respiratory control ratio, increased ATP content, and decreased lag phase. IPC and CCPA also prevented the I/Rinduced susceptibility to calcium-induced mitochondrial permeability transition, the rate of reactive oxygen species (ROS) generation, and the decreased mitochondrial content of phospho-Ser 9 GSK-3β. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3β activity by Aktmediated Ser 9 -GSK-3β phosphorylation preserving the efficiency of oxidative phosphorylation and ROS-mediated cell death in the ability of A1R activation to mimic IPC in the liver. In conclusion, the parallel between IPC and A1R-mediated preconditioning also paves the way to consider a putative therapeutic use of the later in liver transplants.

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…GSK-3β inactivation or GSK-3β-Ser9 phosphorylation maintains the efficiency of oxidative phosphorylation (OXPHOS) and controls the production of ROS. Ischemic preconditioning (IPC) promotes the concentration of phospho-Ser9-GSK-3β in mitochondria, which directly binds to adenine nucleotide translocator (ANT), resulting in modulation of mitochondrial permeability transition (MPT) functions [49]. …”

Purinergic signalling in liver diseases: Pathological functions and therapeutic opportunities

“… 112 IR injury Apyrase 114 and 5′-nucleotidase 115 have hepatoprotective effects. An A1 agonist (CCPA), 113 A2 receptor agonists (CGS-21680, 116 , 117 ATL146e 119 ), and an A3 receptor agonist (CF102) 120 attenuate hepatocyte and sinusoidal endothelial cell apoptosis. Liver transplantation Apyrase 123 and an A2B receptor agonist (CGS21680) 125 , 126 have inflammatory-attenuating effects.…”

“…Ischaemia-reperfusion (IR) injury occurs in many clinical settings, including liver resections, haemorrhagic shock, and liver transplantation, wherein ATP content is reduced in mitochondria isolated from liver tissue, resulting in reactive oxygen species (ROS) generation and Ca 2+ -induced mitochondrial swelling. 113 …”

Electroacupuncture Pretreatment Alleviates Cerebral Ischemia-Reperfusion Injury by Increasing GSK-3β Phosphorylation Level via Adenosine A1 Receptor

“…CCPA is an A1 receptor agonist, and it was found to promote phosphorylation of GSK-3β in a screening trial of protective drugs for myocardial ischemic tolerance [7]. Similarly, in a liver ischemic tolerance test that was mediated by the A1 receptor, CCPA caused a significant increase in P-GSK-3β [8]. GSK-3β is the convergence point of the cellular protective signaling pathway, which plays an important role in the regulation of neuronal polarity, neuroinflammation, and neurodegenerative disorders [9,10].…”