Transferring Protection: Adenosine as the Lone Ranger

Coronary effluent from a heart undergoing brief periods of ischemia and reperfusion that leads to the cytoprotection of ischemic preconditioning decreases injury when administered before ischemia to a second heart; the “transfer of cardioprotection” phenomena [1]. In the current issue of Cardiovascular Drugs and Therapy, Dr. Leung and colleagues replicate the “transfer of cardioprotection” in an isolated rabbit heart model [2]. The authors hypothesize that increased adenosine content in coronary effluent from the first ischemic preconditioned heart is the key mediator of the protection transferred to the second heart. Four lines of evidence support their hypothesis: (1) the content of adenosine in collected coronary effluent from preconditioned hearts is dramatically increased; (2) the phenomena of “transfer protection” is blocked by a non-selective adenosine receptor inhibitor; (3) direct addition of adenosine into coronary effluent from nonpreconditioned hearts provides a similar reduction in infarct size compared to coronary effluent from the preconditioned hearts; (4) mitochondrial function is improved in hearts treated by coronary effluent from preconditioned hearts. They conclude that the “transfer of protection” is mediated by an increased adenosine content in coronary effluent through preservation of mitochondrial integrity. Activation of adenosine receptors provides solid cardioprotection in experimental hearts following ischemiareperfusion [2–4]. Adenosine treatment also tended to improve outcome in a meta-analysis of clinical trials [5], though outcomes did not reach statistical significance [5], mirroring the failure to demonstrate benefit in the largest single trial [6]. Ischemic damage to mitochondria is a key mechanism of cardiac injury during reperfusion [7]. Protection of mitochondria during ischemia decreases cardiac injury during the subsequent reperfusion [8]. In Dr. Leung’s study, perfusion of collected coronary effluent from preconditioned hearts before ischemia improved the mitochondrial function in the recipient heart, supporting the notion that “transfer cardioprotection” is mediated by mitigating mitochondrial damage during ischemia-reperfusion. Although addition of adenosine into control coronary effluent reduces the infarct size to a similar extent as treatment by coronary effluent from preconditioned hearts, there are different effects on mitochondrial function between these two treatments. Ischemic preconditioning protects mitochondria through inhibition of mitochondrial permeability transition pore (MPTP) [9]. The MPTP is also inhibited in hearts treated by ischemic postconditioning [10, 11]. In the current study, mitochondrial respiration and the integrity of outer mitochondrial membrane are significantly improved in coronary effluent treated hearts. However, pure adenosine treatment improved outer membrane integrity but did not protect the electron transport chain. The adenosine treatment results in a better coupled mitochondrial respiration through an unclear mechanism. These results suggest that adenosine is not the sole substance that induces the transferred protection. Other molecular entities, especially small peptides, may contribute to this protection [12]. The preliminary proteomic study is an exciting step to further clarify the molecular targets in this Q. Chen : E. J. Lesnefsky Department of Medicine (Division of Cardiology, Pauley Heart Center), Virginia Commonwealth University, Richmond, VA 23298, USA