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

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Abstract

Although adenosine A1 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-N6-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-Ser9 GSK-3β. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3β activity by Akt-mediated Ser9-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.

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Abbreviations

A1R:

Adenosine A1 receptor

ALT:

Alanine aminotransferase

ANT:

Adenine nucleotide translocator

AST:

Aspartate aminotransferase

CypD:

Cyclophilin D

CCPA:

2-Chloro-N6-cyclopentyladenosine

H2DCF-DA:

2′,7′-Dichlorodihydrofluorescein diacetate

DPCPX:

8-Cyclopentyl-1,3-dipropylxanthine

FCCP:

Carbonylcyanide-p-trifluoromethoxyphenylhydrazon

GSK-3β:

Glycogen synthase kinase-3β

IPC:

Ischemic preconditioning

I/R:

Ischemia/reperfusion

LDH:

Lactate dehydrogenase

ΔΨ:

Mitochondrial membrane potential

MPT:

Mitochondrial permeability transition

OXPHOS:

Oxidative phosphorylation

PC:

Preconditioning

RCR:

Respiratory control ratio

RFUs:

Relative fluorescence units

ROS:

Reactive oxygen species

TPP+ :

Tetraphenylphosphonium

VDAC:

Voltage-dependent anion channel

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Authors and Affiliations

  1. CNC–Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal

    Filipe V. Duarte, João A. Amorim, Ana T. Varela, João S. Teodoro, Ana P. Gomes, Rodrigo A. Cunha, Carlos M. Palmeira & Anabela P. Rolo

  2. Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-504, Coimbra, Portugal

    Filipe V. Duarte, Ana T. Varela, João S. Teodoro, Ana P. Gomes, Carlos M. Palmeira & Anabela P. Rolo

  3. FMUC–Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal

    Rodrigo A. Cunha

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  1. Filipe V. Duarte
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Correspondence to Anabela P. Rolo.

Ethics declarations

All animals received care according to institutional guidelines, and all procedures were according to EU guidelines (2010/63) after approval by the Animal Care Committee of the University of Coimbra.

Grants and financial support

This study is funded by FEDER through COMPETE 2020 and Fundação para a Ciência e a Tecnologia (UID/NEU/04,539/2013). FVD and JST are recipients of a Portuguese Foundation for Science and Technology post-doctoral scholarship (SFRH/BPD/94,898/2013 and SFRH/BPD/94,036/2013, respectively).

Conflict of interest

Filipe V. Duarte declares that he has no conflict of interest.

João A. Amorim declares that he has no conflict of interest.

Ana T. Varela declares that she has no conflict of interest.

João S. Teodoro declares that he has no conflict of interest.

Ana P. Gomes declares that she has no conflict of interest.

Rodrigo A. Cunha declares that he has no conflict of interest.

Carlos M. Palmeira declares that he has no conflict of interest.

Anabela P. Rolo declares that she has no conflict of interest.

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Duarte, F.V., Amorim, J.A., Varela, A.T. et al. Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver. Purinergic Signalling 13, 179–190 (2017). https://doi.org/10.1007/s11302-016-9548-x

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