Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion

Abstract

Short non-lethal ischemic episodes administered to hearts prior to (ischemic preconditioning, IPC) or directly after (ischemic postconditioning, IPost) ischemic events facilitate myocardial protection. Transferring coronary effluent collected during IPC treatment to un-preconditioned recipient hearts protects from lethal ischemic insults. We propose that coronary IPC effluent contains hydrophobic cytoprotective mediators acting via PI3K/Akt-dependent pro-survival signaling at ischemic reperfusion. Ex vivo rat hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion. IPC effluent administered for 10 min prior to index ischemia attenuated infarct size by ≥55% versus control hearts (P < 0.05). Effluent administration for 10 min at immediate reperfusion (reperfusion therapy) or as a mimetic of pharmacological postconditioning (remote postconditioning, RIPost) significantly reduced infarct size compared to control (P < 0.05). The IPC effluent significantly increased Akt phosphorylation in un-preconditioned hearts when administered before ischemia or at reperfusion, while pharmacological inhibition of PI3K/Akt-signaling at reperfusion completely abrogated the cardioprotection offered by effluent administration. Fractionation of coronary IPC effluent revealed that cytoprotective humoral mediator(s) released during the conditioning phase were of hydrophobic nature as all hydrophobic fractions with molecules under 30 kDa significantly reduced infarct size versus the control and hydrophilic fraction-treated hearts (P < 0.05). The total hydrophobic effluent fraction significantly reduced infarct size independently of temporal administration (before ischemia, at reperfusion or as remote postconditioning). In conclusion, the IPC effluent retains strong cardioprotective properties, containing hydrophobic mediator(s) < 30 kDa offering cytoprotection via PI3K/Akt-dependent signaling at ischemic reperfusion.

Myocardial triggers involved in activation of remote ischaemic preconditioning

“…From this point of view, several studies have evaluated the intracellular signalling pathway involved in the cardioprotection afforded by rIPC (Wolfrum et al 2002;Li et al 2010;Breivik et al 2011). However, those authors have not considered the timing sequence of signalling activation.…”

Sanguinarine Non- Versus Re-Circulation During Isolated Heart Perfusion - A Jekyll and Hyde Effect?

“…insulin improved functional recovery in the older animals, the focal point of this article is to show how variances in outcomes can occur with the same drug with different modes of delivery. It has been shown that coronary effluent from hearts which have undergone prior ischaemic preconditioning contained cytoprotective factors that, when transferred to other hearts, offers protection (9). However to our knowledge our study is novel in that the hearts were not preconditioned, the coronary effluent was used on the same hearts by which it was produced and sanguinarine was the only drug used which caused this effect.…”

Methylophiopogonanone A suppresses ischemia/reperfusion-induced myocardial apoptosis in mice via activating PI3K/Akt/eNOS signaling pathway

“…Previous studies demonstrated that some signaling molecules were thought to serve as the upstream mediators of apoptosis during I/R injury [7,9] . The PI3K/Akt pathway is central to physical and pharmacological pre-and post-conditioning and salvaging the ischemia/reperfused myocardium [23][24][25][26] . It has been…”