Sphingosine 1-Phosphate Postconditioning Protects Against Myocardial Ischemia/reperfusion Injury in Rats via Mitochondrial Signaling and Akt-Gsk3β Phosphorylation.

Although preconditioning of sphingosine 1-phosphate (S1P) has been shown to protect myocytes from hypoxia reoxgenation injury in vitro, the role of S1P postconditioning on myocardial ischemia reperfusion injury (MIRI) in vivo and its related mechanism are unknown. The aim of this study was to investigate the protective role of sphingosine 1-phosphate (S1P) postconditioning in MIRI via its effects on mitochondrial signaling and Akt/Gsk3β phosphorylation. Rats were subjected to MIRI, consisting of 30 min of ischemia followed by 120 min of reperfusion, with S1P administered at the beginning of the reperfusion. Myocardial infarct size and apoptotic index were measured by triphenyltetrazolium (TTC) and terminal deoxynucleotide transferase dUTP nick-end labeling (TUNEL) assays, respectively. Akt and Gsk3β phosphorylation, caspase-3 cleavage, and cytochrome c translocation were assessed by western blot. Mitochondrial permeability transition pore (MPTP) opening and mitochondrial membrane potential (MMP, ΔΨ) were also examined to determine overall mitochondrial function. S1P postconditioning significantly decreased myocardial infarct size and apoptosis, as well as enhanced Akt and Gsk3β phosphorylation, attenuated caspase-3 cleavage and cytosolic cytochrome c translocation, and inhibited MPTP opening, which subsequently preserved Δψ. Electron microscopy also confirmed that S1P helped maintain myocardial mitochondria integrity. Moreover, the protective effects of S1P treatment were blocked by cotreatment with a PI3K inhibitor, LY294002. These results suggest that S1P postconditioning protects against MIRI by regulating mitochondrial signaling and Akt/Gsk3β phosphorylation.

Fang R ，Zhang LL ，Zhang LZ ，Li W ，Li M ，Wen K ... -  《-》

Rosuvastatin postconditioning protects isolated hearts against ischemia-reperfusion injury: The role of radical oxygen species, PI3K-Akt-GSK-3β pathway, and mitochondrial permeability transition pore.

Glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore (mPTP) play an important role in myocardial ischemia-reperfusion injury. The aim of this study was to investigate whether postconditioning with rosuvastatin is able to reduce myocardial ischemia-reperfusion injury and clarify the potential mechanisms. Isolated rat hearts underwent 30 minutes of ischemia and 60 minutes of reperfusion in the presence or absence of rosuvastatin (1-50 nmol/L). The activity of signaling pathway was determined by Western blot analysis, and Ca2+ -induced mPTP opening was assessed by the use of a potentiometric method. Rosuvastatin significantly reduced myocardial infarct size and improved cardiac function at 5 and 10 nmol/L. Protection disappeared at higher concentration and reverted to increased damage at 50 nmol/L. At 5 nmol/L, rosuvastatin increased the phosphorylation of protein kinase B (Akt) and GSK-3β, concomitant with a higher Ca2+ load required to open the mPTP. Rosuvastatin postconditioning also significantly increased superoxide dismutase activity and reduced malondialdehyde and radical oxygen species level. LY294002, phosphatidylinositol-3-kinase (PI3K) inhibitors, abolished these protective effects of rosuvastatin postconditioning. Rosuvastatin prevents myocardial ischemia-reperfusion injury by inducing phosphorylation of PI3K-Akt and GSK-3β, preventing oxidative stress and subsequent inhibition of mPTP opening.

Liu CW ，Yang F ，Cheng SZ ，Liu Y ，Wan LH ，Cong HL ... -  《-》

Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta.

Feng J ，Lucchinetti E ，Ahuja P ，Pasch T ，Perriard JC ，Zaugg M ... -  《ANESTHESIOLOGY》

Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion.

Gomez L ，Paillard M ，Thibault H ，Derumeaux G ，Ovize M ... -  《-》

Attenuation of ischemia-reperfusion injury by sevoflurane postconditioning involves protein kinase B and glycogen synthase kinase 3 beta activation in isolated rat hearts.

Fang NX ，Yao YT ，Shi CX ，Li LH ... -  《-》