Postconditioning: A new link in nature’s armor against myocardial ischemia/reperfusion injury Gao Qin

Definition of postconditioning Postconditioning is defined as a series of brief interruptions of reperfusion applied at the very onset of reperfusion This algorithm is “on-off” episodes of reperfusion

Models of postconditioning Postconditioning has been reported in multiple models including : small and large animal models in vitro organ perfusion system Cell culture model

Postconditioning algorithm Heart model The number of cycles 3 cycles ~ 6 cycles The duration of reocclusion and reperfusion episodes 10 seconds ~ 60 seconds Cardiomyocyte 3 cycles of 5 min of reoxygenation and 5 min re-hypoxia

Postconditioning algorithm Related to the species of animal In rat heartIn rabbit heart

Mechanisms in postconditioning Area at risk myocardium after reperfusion harvested and stained with Dihydroethidium fluorescence (DHE) to visually assess generation of superoxide anions. A: IR group; B and C: area at risk myocardium from IPC and Post-con hearts, respectively; D: Delayed Post-con group. Fluorescence photomicrographs with DHE showing in situ detection of superoxide in the nonischemic (A, control and C, Post-con) and ischemic (B, Control and D, Post-con) myocardium after ischemia and reperfusion. Arrows indicate small vessels in myocardium.

Mechanisms in postconditioning Mitochondrial calcium ([Ca 2+ ]m) uptake measured by fluorescent X-rhod-1 AM staining. Significantly increased [Ca 2+ ]m uptake relative to the Sham control was detected after 3 h hypoxia (H) and 6 h of re-oxygenation (Re). Post-con significantly reduced [Ca 2+ ]m relative to H/Re.

Mechanisms in postconditioning Adenosine K ATP channels Rat modelRabbit model In isolated rabbit model

Mechanisms in postconditioning Nitric oxide L-NAME and ODQ completely inhibited the infarct sparing effects of postconditioning — NO –cGMP pathway Postconditioning in canine model Attenuate P-selectin expression Decrease MPO activity: a marker of neutrophil accumulation in myocardium Improve vasodilator responses to acetylcholine — s uggest vascular endothelium releases NO

Mechanisms in postconditioning Reperfusion injury survival kinases (RISK) (MEK) 1/2 and ERK inhibitor PD inhibited the infarct sparing effect of postconditioning PI3-kinase inhibitors LY or wortmannin inhibited the infarct-sparing effect of postconditioning

Mechanisms in postconditioning Reperfusion injury survival kinases (RISK) LY or wortmannin decrease myocardial p-Akt levels (a downstream marker of PI3-kinase activity),p-eNOS and p-p70s6K Representative Western blots demonstrating phosphorylated and total protein levels. Results show that inhibiting PI3K abolishes phosphorylation of Akt (A), eNOS (B), and p70S6K (C) induced by ischemic postconditioning

Mechanisms in postconditioning Mitochondrial permeability transition pore The Ca 2+ load that induced MPTP opening in postconditioning group significantly higher than in ischemia and reperfusion group Post-C

Mechanisms in postconditioning adenosine (ADO) adenosinergic G-protein coupled receptor (GPCR) Cardiomyocytes (CMC)

Mechanisms in postconditioning

Relationship between preconditioning and postconditioning In rabbit heart in vivo 45min coronary occlusion and 3h reperfusion In rat heart in vitro 35min coronary occlusion and 2h reperfusion

Relationship between preconditioning and postconditioning

The second window? Unpublished data suggest that the infarct reduction achieved by postconditioning persists for 24 hours (Zhao)

Pharmacological postconditioning Agents were administered at reperfusion — adenosine and analogs, nitric oxide, insulin, statins, opioids, volatile anesthetics