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

作者：Duarte Filipe V; Amorim Joao A; Varela Ana T; Teodoro Joao S; Gomes Ana P; Cunha Rodrigo A; Palmeira Carlos M; Rolo Anabela P^*

来源：Purinergic Signalling, 2017, 13(2): 179-190.

DOI：10.1007/s11302-016-9548-x

• Adenosine A1 receptors
• GSK-3 beta
• glycogen synthase kinase 3 beta
• Ischemic preconditioning
• Liver
• Mitochondrial permeability transition
• Oxidative phosphorylation

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/R-induced 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-3 beta. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3 beta activity by Akt-mediated Ser(9)-GSK-3 beta 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.

• 出版日期2017-6