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. 2011 Jan;106(1):135-45.
doi: 10.1007/s00395-010-0133-0. Epub 2010 Nov 20.

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

L Breivik  1 , E Helgeland, E K Aarnes, J Mrdalj, A K Jonassen
Affiliations

Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion (V体育安卓版)

L Breivik et al. Basic Res Cardiol. 2011 Jan.

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) VSports手机版. 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. .

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Fig. 1
Fig. 1
Experimental protocols. All groups were subjected to 30 min of regional ischemia (RI) followed by 120 min of reperfusion. Hearts receiving no other treatments constitute the control group (Ctr). a The IPC group was exposed to 3× 5 min global ischemia (GI), with 5 min intermittent reperfusion periods prior to RI. To test the temporal cytoprotective efficacy of IPC effluent in recipient hearts, freshly collected effluent was administered for 10 min prior to RI (EffPre) or for 10 min at onset of ischemic reperfusion (EffRep). Furthermore, to mimic ischemic postconditioning, the IPC effluent was administered for 3× 30 s with 30 s intermittent KHB perfusion at immediate reperfusion (EffPost). Ischemic postconditioning (IPost) was achieved by 3× 30 s of global ischemia (GI) at early ischemic reperfusion. The PI3K-inhibitor WI (1 μM) and the Akt-inhibitor SH-6 (10 μM) were administered for 10 min at immediate onset of ischemic reperfusion in conjunction with 10 min of pre- or post-ischemic treatment with IPC effluent (EffPre + WI/SH-6, EffRep + WI/SH-6 or EffPost + WI). b The IPC effluent was fractionated in respect to charge and size. Effluent collected during IPC was first separated into a hydrophilic (HPhil) and a hydrophobic (HPhob) fraction. All total effluent fractions were administered for either 10 min prior to ischemia (HPhilPre and HPhobPre) or for 10 min at reperfusion (HPhobRep and HPhobPost). The hydrophobic fraction was further fractionated by a 10 or 30 kDa size filter resulting in four hydrophobic fractions with molecules below 10/30 kDa (HPhobPre < 10 and HPhobRep < 30) or above 10/30 kDa (HPhobPre > 10 and HPhobRep > 30). Arrows indicate time points for tissue sampling. Solid lines KH buffer perfusion
Fig. 2
Fig. 2
The temporal effect of treatment with IPC effluent on myocardial infarct size. Infarct size is expressed as percentage of the region at risk of infarction (area at risk). Effluent from preconditioned donor hearts (IPC) administered either 10 min prior to index ischemia (EffPre) or for 10 min at ischemic-reperfusion (EffRep) significantly reduced infarct size in non-preconditioned recipient hearts as compared to controls (Ctr). Bars represent mean ± SEM. N ≥ 7 in each group. *P < 0.05 versus Ctr group
Fig. 3
Fig. 3
The effect of administering IPC effluent as a mimetic of ischemic postconditioning (RIPost) on myocardial infarct size. Treatment of recipient hearts with IPC effluent for 3× 30 s at ischemic reperfusion (EffPost) reduced infarct size to the same extent as ischemic postconditioning (IPost), and both groups had significantly reduced infarct size as compared to the control group (Ctr). Bars represent mean ± SEM. N ≥ 7 in each group. *P < 0.05 versus Ctr
Fig. 4
Fig. 4
Phosphorylation status of myocardial Akt in recipient hearts exposed to treatment with IPC effluent. a Representative immunoblots of Akt phosphorylation (Ser473) showing the effects of treatment with IPC effluent (EffPre) in recipient hearts (tissue harvested at end of treatment), as compared to hearts exposed to the standard IPC protocol (IPC) and baseline hearts (C B). c Representative immunoblots of Akt phosphorylation (Ser473) in pre-ischemic IPC effluent-treated hearts that was also reperfused for 15 min (EffPre+Rep) and reperfusion treatment with IPC effluent (EffRep) in recipient hearts as compared to ischemic reperfused control hearts (CtrRep) (tissues harvested at 15 min of reperfusion). Administering the PI3K-inhibitor WI (1 μM) and the Akt-inhibitor SH-6 (10 μM) for 10 min at reperfusion abrogated Akt phosphorylation in IPC effluent-treated hearts. Total Akt and GADPH indicates equal loading. b, d Densitometric analysis of total and phosphorylated Akt immunoblots expressed in arbitrary units (AU). p-Akt expressed as a ratio of total Akt with C B = 1. Bars represent mean ± SEM. N ≥ 3 in each group. *P < 0.05 versus C B, † P < 0.05 versus IPC, § P < 0.05 versus EffPre+Rep, ¤ P < 0.05 versus EffRep, # P < 0.05 versus CtrRep
Fig. 5
Fig. 5
The effect of inhibiting PI3K and Akt upon reperfusion in IPC effluent-treated recipient hearts. When administering the PI3K-inhibitor WI and the Akt-inhibitor SH-6 at the onset of reperfusion in IPC effluent pre-ischemic (EffPre) or post-ischemic (EffRep and EffPost) treated hearts, the cardioprotective effect of the effluent was completely abolished. Ctr control; Eff Pre 10 min effluent administration prior to RI; Eff Rep 10 min effluent administration after RI; Eff Post effluent administration 3× 30 s at start of reperfusion; WI 10 min Wortmannin (1 μM) at reperfusion; SH-6 10 min SH-6 (10 μM) at reperfusion. Bars represent mean ± SEM. N ≥ 6 in each group. *P < 0.05 versus Ctr
Fig. 6
Fig. 6
The effect of fractionating the IPC effluent based on charge and size with regard to myocardial infarct size. Pre- or post-ischemic administration of the total hydrophobic fraction (HPhobPre, HPhobRep and HPhobPost) and the fractions containing proteins < or >10 kDa (HPhobPre < 10 and HPhobPre > 10) and <30 kDa (HPhobRep < 30) significantly reduced infarct size in non-preconditioned recipient hearts as compared to hydrophilic effluent (HPhil) and control (Ctr) hearts. The hydrophobic fraction containing proteins >30 kDa (HPhobRep < 30) did not offer any cytoprotection. HPhil effluent not bound to C18 column; HPhob effluent eluted from C18 column; total entire hydrophobic fraction; < or >10/30 kDa total hydrophobic fraction further separated by a size exclusion column. Bars represent mean ± SEM. N ≥ 5 in each group. *P < 0.05 versus Ctr
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