Distinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning

Abstract

Cardioprotection against ischaemia/reperfusion injury in mice can be achieved by delayed ischaemic postconditioning (IPost) applied as late as 30 min after the onset of reperfusion. We determined the efficacy of delayed IPost in a rat model of myocardial infarction (MI) and investigated potential underlying mechanisms of this phenomenon. Rats were subjected to 20, 30 or 45 min of coronary artery occlusion followed by 120 min of reperfusion (I/R). Immediate and early IPost included six cycles of I/R (10/10 s) applied 10 s or 10 min after reperfusion onset. In the second series of experiments, the rats were subjected to 30 min of coronary occlusion followed by IPost applied 10 s, 10, 30, 45 or 60 min after the onset of reperfusion. Immediate and early IPost (applied 10 s or 10 min of reperfusion) established cardioprotection only when applied after a period of myocardial ischaemia lasting 30 min. Delayed IPost applied after 30 or 45 min of reperfusion reduced infarct sizes by 36 and 41 %, respectively (both P < 0.01). IPost applied 60 min after reperfusion onset was ineffective. Inhibition of RISK pathway (administration of ERK1/2 inhibitor PD-98059 or PI3K inhibitor LY-294002) abolished cardioprotection established by immediate IPost but had no effect on cardioprotection conferred by early IPost. Blockade of SAFE pathway using JAK/STAT inhibitor AG490 had no effect on the immediate or early IPost cardioprotection. Blockade of mitochondrial KATP (mitoKATP) channels (with 5-Hydroxydecanoate) abolished cardioprotection achieved by immediate and early IPost, but had no effect on cardioprotection when IPost was applied 30 or 45 min into the reperfusion period. Immediate IPost increased phosphorylation of PI3K-AKT and ERK1/2. Early or delayed IPost had no effect on phosphorylation of PI3K-AKT, ERK1/2 or STAT3. These data show that in the rat model, delayed IPost confers significant cardioprotection even if applied 45 min after onset of reperfusion. Cardioprotection induced by immediate and early postconditioning involves recruitment of RISK pathway and/or mitoKATP channels, while delayed postconditioning appears to rely on a different mechanism.

Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137

“…However, Lambert et al (2014) demonstrated that in diabetic rats NaSH-induced postconditioning might signal through the other arm of the RISK pathway, namely ERK1/2. LY294002 alone had no significant effect on either the infarct size or Akt phosphorylation compared to control which is consistent with the findings of other investigators , Barsukevich et al, 2015.…”

Delayed low pressure at reperfusion: A new approach for cardioprotection

“…However, delayed LPR (from 10 minutes) did not preserve PI3K activation ( Figure E1, A and B). This last observation was confirmed in the study by Barsukevich and colleagues,5 in which delayed postconditioning did not induce phosphorylation of Akt, Erk ½, and Stat. Thus, it can be suggested that distinct cardioprotective mechanisms seem to be involved between early postconditioning-LPR (which implies Akt-P and Erk-P) and late LPR.…”

“…[1][2][3] This very narrow therapeutic time window may limit postconditioning application in the clinical setting. Two recent studies proposed that the protective effect of ischemic postconditioning may persist even when applied several minutes after reflow in the in vivo mouse 4 and rat 5 models, but the mechanism of protection remains to be determined. By invalidation of the prevailing concept, these new studies open a new way for cardioprotection.…”

“…1-3 Furthermore, postconditioning studies on other organs (brain, 21 lung, 22 intestines 23 ) failed when the maneuver was applied after a delay of only 3 minutes. However, 2 recent articles evidenced that ischemic postconditioning might still reduce infarct size when the protective stimulus was delayed as long as 45 minutes for rats 5 and 30 minutes for mice 4 after reflow. These new studies question the timing and optimization of the cardioprotective interventions applied at reperfusion.…”

Controlled Reperfusion Strategies Improve Cardiac Hemodynamic Recovery after Warm Global Ischemia in an Isolated, Working Rat Heart Model of Donation after Circulatory Death (DCD)

“…Identification of robust cardioprotective reperfusion strategies has been the subject of intense research activity for several years, but promising pre-clinical approaches have seldom provided convincing cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI) (Downey and Cohen, 2009; Lloyd-Jones, 2010; Kloner, 2013; Bulluck et al, 2016). This might be explained by interfering effects of co-morbidities and/or concomitant therapies (Hausenloy and Yellon, 2004; Bell and Yellon, 2012), delayed application of cardioprotective strategies (Roubille et al, 2014) and/or too long or too short ischemia (Barsukevich et al, 2015). However, with DCD cardiac grafts, donors will be subject to donor selection, and thus patients will generally be young and healthy, thereby limiting possible negative effects associated with comorbidities and medical therapies.…”