Combined local ischemic postconditioning and remote perconditioning recapitulate cardioprotective effects of local ischemic preconditioning.
Ischemic postconditioning (PostC) and perconditioning (PerC) provide practical methods for protecting the heart against ischemia-reperfusion (I/R) injury, but their combined effects have not been studied in detail. Using an in vivo rat I/R model, we tested 1) whether additive effects were produced when local PostC was preceded by varying doses of remote PerC, and whether the optimal PostC+PerC regime is additive to local ischemic preconditioning (IPC), and 2) how combined PostC+PerC alters the activity of the reperfusion injury salvage kinase pathway. The optimal combination of PerC and PostC therapy was produced by PerC delivered with four cycles of 5 min of limb ischemia followed by 5-min reperfusion. This resulted in lower infarct size (22.56 +/- 4.45%) compared with rats with PostC alone (29.39 +/- 3.66%) and PerC alone (33.49 +/- 5.81%) and complementary differences in the generation of reactive oxygen species and apoptotic signaling. However, this optimal combination of PostC+PerC resulted in protection similar to local IPC alone (18.8 +/- 2.54%, P = 0.13), and when added to IPC there was no additional protection (19.62 +/- 2.89%, P = 0.675). Akt and ERK1/2 phosphorylation was induced by PostC and PerC and maximally by combined PostC+PerC treatment, and protection was abolished by phosphatidylinositol 3-kinase or ERK1/2 inhibitors. This study shows that neither PostC nor a maximized "dose" of PerC leads to optimal kinase signaling or cardioprotection compared with IPC alone. However, combined PostC+PerC may result in complementary effects on kinase signaling to recapitulate the effects of local IPC. Finally, combined PostC+PerC is not additive to IPC, suggesting that each works via a common pathway.
Xin
Ping
P
Division of Cardiology, Shanghai Sixth Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Zhu
Wei
W
Li
Jing
J
Ma
Shixin
S
Wang
Lixing
L
Liu
Mingya
M
Li
Jingbo
J
Wei
Meng
M
Redington
Andrew N
AN
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
D017382:Reactive Oxygen Species; D013481:Superoxides; D008315:Malondialdehyde; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases