Postconditioning: A new link in nature's armor against myocardial ischemia/reperfusion injury Gao Qin 2005-4-29
Postconditioning: A new link in nature’s armor against myocardial ischemia/reperfusion injury Gao Qin 2005-4-29
星 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 Control 30 min I 3hR IPC ■ 5minl 10minR 30 min I 3hR Post-con I ■ 民1民 3h R Post-con 2 30 min I 3hR Delay Post-con☐ 30 min I 3h R
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
3铺 scEncE Models of postconditioning Postconditioning has been reported in multiple models including small and large animal models in vitro organ perfusion system Cell culture model
Models of postconditioning • Postconditioning has been reported in multiple models including : • small and large animal models • in vitro organ perfusion system • Cell culture model
3铺 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 Post-con I 30 min I RIRIR1 3bR Post-con 2 000000 30 min I 3h R
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 r 60 40 10 Cntl 3x3x3x 6x 30R30R+15R+10R 10R+ +301151151 101 In rat heart In rabbit heart
Postconditioning algorithm • Related to the species of animal In rat heart In rabbit heart
3 scEncE Mechanisms in postconditioning Area at risk myocardium after reperfusion Fluorescence photomicrographs with DHE harvested and stained with Dihydroethidium showing in situ detection of superoxide in the fluorescence(DHE)to visually assess generation of nonischemic (A,control and C,Post-con)and superoxide anions.A:IR group;B and C:area at ischemic (B,Control and D,Post-con) risk myocardium from IPC and Post-con hearts. myocardium after ischemia and reperfusion respectively:D:Delayed Post-con group. Arrows indicate small vessels in myocardium
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 Sham H/Re Post-con Mitochondrial calcium([Ca2+]m)uptake measured by fluorescent X-rhod-1 AM staining.Significantly increased [Ca2+]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 [Ca2+]m relative to H/Re
Mechanisms in postconditioning Mitochondrial calcium ([Ca2+ ]m) uptake measured by fluorescent X-rhod-1 AM staining. Significantly increased [Ca2+ ]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 [Ca2+ ]m relative to H/Re
3 NscEncE Mechanisms in postconditioning ·Adenosine Karp channels 60 30-min lschemla 48.848 o 000 8 8 S 20 8 10 Cntl Postc 8-p- 8-0-SPT SPT +PostC In isolated rabbit model Control 4 cyc Glib 5-HD AN/AAR Rat model Rabbit model
Mechanisms in postconditioning • Adenosine • KATP channels Rat model Rabbit model In isolated rabbit model
scEncE 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 120 -suggest vascular endothelium 80 releases NO 60 20 0.00 0.01 0.1 Acetycholine (uM)
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 — suggest vascular endothelium releases NO
Mechanisms in postconditioning Reperfusion injury survival kinases (RISK) (MEK)1/2 and ERK inhibitor PD-98059 inhibited the infarct sparing effect of postconditioning PI3-kinase inhibitors LY294002 or wortmannin inhibited the infarct-sparing effect of postconditioning 60 30-min lachemia 50 8 8, 50 4 8 5HD L-NAME Cont 4 cycle 4 cycles
Mechanisms in postconditioning • Reperfusion injury survival kinases (RISK) • (MEK) 1/2 and ERK inhibitor PD-98059 inhibited the infarct sparing effect of postconditioning • PI3-kinase inhibitors LY294002 or wortmannin inhibited the infarct-sparing effect of postconditioning