Does ischemic preconditioning increase flap survival by ADORA2B receptor activation?

Article type: Research Article

Authors: Ulker, Pinar^{a; 1} | Ozkan, Ozlenen^{b; 1} | Amoroso, Matteo^{c; 1} | Aslan, Mutay^d | Bassorgun, Ibrahim^e | Ubur, Mehmet Can^b | Ünal, Kerim^b | Ozcan, Filiz^d | Ozkan, Omer^{b; *}

Affiliations: [a] Department of Physiology, Akdeniz University, Antalya, Turkey | [b] Department of Plastic and Reconstructive Surgery, Akdeniz University, Antalya, Turkey | [c] Department of Plastic Surgery, University of Gothenburg, The Sahlgrenska Academy, Institute of Clinical Sciences, Sahlgrenska University Hospital, Göteborg, Sweden | [d] Department of Biochemistry, Akdeniz University, Antalya, Turkey | [e] Department of Pathology, Akdeniz University, Antalya, Turkey

Correspondence: [*] Corresponding author: Omer Ozkan, Department of Plastic and Reconstructive Surgery, Akdeniz University School of Medicine, Antalya 07070, Antalya, Turkey. E-mail: [email protected].

Note: [1] Pinar Ulker, Ozlenen Ozkan and Matteo Amoroso contributed equally to this work and share first authorship.

Abstract: BACKGROUND:Ischemic preconditioning (IPC) is defined as raising tolerance to subsequent ischemic stress by exposing tissues to sub-lethal ischemia. Although many candidates have been suggested, recent studies have clearly demonstrated that adenosine-mediated ADORA2B receptor (ADORA2BR) activation is the main mechanism involved in IPC. While the tissue-protective role of this mechanism has been demonstrated in different ischemia/reperfusion (I/R) models, its role in flap surgery-derived I/R damage has not to date been investigated. OBJECTIVE:To investigate the role of adenosine and ADORA2BR activation in IPC-mediated tissue protection in an epigastric flap model. METHODS:Animals were divided into five main groups, all of which were then divided into two subgroups depending on whether or not they were exposed to IPC before the I/R procedure, which consisted of 6 hours of ischemia and 6 days of reperfusion. No drugs were administered in Group 1 (the control group). Animals in Group 2 were pretreated with CD73-inhibitor before IPC application or the ischemic period. Animals in Group 3 were pretreated with adenosine. Animals in Group 4 were pretreated with an ADORA2BR antagonist, and those in Group 5 with an ADORA2BR agonist. After 6 days of reperfusion, tissue survival was evaluated via histological and macroscopic analysis. RESULTS:IPC application significantly enhanced CD73 expressions and adenosine concentrations (p < 0.01). Flap survivals were increased by IPC in Group 1 (p < 0.05). However, CD73 inhibition blocked this increase (Group 2). In Group 3, adenosine improved flap survival even in the absence of IPC (p < 0.01). While an ADORA2BR antagonist attenuated the tissue-protective effect of IPC (p < 0.01), the ADORA2BR agonist improved flap survival by mimicking IPC in groups 4 and 5. CONCLUSION:These results provide pharmacological evidence for a contribution of CD73 enzyme-dependent adenosine generation and signaling through ADORA2BR to IPC-mediated tissue protection. They also suggest for the first time that ADORA2BR agonists may be used as a potential preventive therapy against I/R injury in flap surgeries.

Keywords: Adenosine, ADORA 2B, ischemia, reperfusion, flap survival

DOI: 10.3233/CH-190730

Journal: Clinical Hemorheology and Microcirculation, vol. 75, no. 2, pp. 151-162, 2020