| Aim:Sevoflurane postconditioning (sevo-postC) could reduce myocardial infarct size in various young amimal models. However, it is unknown whether the cardioprotective effects are still effective in old rats. So, our purpose is to investigate whether there are age-related differences in response to myocardial ischemia-reperfusion injury and sevoflurane postconditioning in rats in vivo, as well as address the underlying mechanisms.Methods:Young and old rats were subjected to30min of myocardial ischemia, induced by left anterior descending coronary artery occlusion, followed by2h of reperfusion with or without sevo-postC, administered by inhalation of1.0or2.0MAC (mimimal alveolar concentration) sevoflurane initiated immediately upon reflow for5min. In some experiments, PI3K, MEK1/2or JAK2inhibitor was coadministered with sevoflurane. Primary endpoints include myocardial infarct size (IS), cardiomyocyte apoptotic index (AI), serum cardiac troponin I (cTnI) and cardiac NAD+level, indicative of opening of mitochondrial permeability transition pore (mPTP). Cardiac expression level of phosphorylated protein kinase B (Akt), extra-cellular signal-regulated kinase1/2(ERK1/2) and signal transducer and activator of transcription3(STAT3) were determined by western blotting.Results:In young rats, either1.0or2.0MAC sevo-postC led to significant reduction of IS (34±3%and32±2%vs.58±5%, P<0.05), lower cTnI level (43.19±3.37ng/ml and41.04±3.38ng/ml vs.71.76±4.74ng/ml, P<0.05) and lower AI (8±1%and7±1%vs.15±2%, P<0.05) compared with control group, but there was no difference in IS, AI and cTnI level between1.0and2.0MAC sevo-postC group (P>0.05). Meanwhile, either1.0or2.0MAC sevo-postC induced a substantial elevation of phosphorylation of Akt (0.72q0.03arbitrary units and0.75±0.03arbitrary units vs.0.32±0.02arbitrary units, P<0.01) and ERK1/2(0.86±0.03arbitrary units and0.88±0.03arbitrary units vs.0.22±0.01arbitrary units, P0<.01) compared to control group, but there was no difference in phosphorylated Akt and ERK1/2between1.0and2.0MAC sevo-postC group (P>0.05). Additionally, the infarct-sparing effect mediated by either1.0or2.0MAC sevo-postC was abrogated by either PI3K or MEK1/2inhibitor, which also inhibited the elevation of phosphorylation of Akt or ERK1/2respectively. The significant reduction of infarct size induced by2.0MAC sevo-postC was not abolished by JAK2inhibitor.However, the infarct-limiting effect elicited by either1.0or2.0MAC sevo-postC in young rats was attenuated in old rats. There was no difference in IS among control group,1.0and2.0MAC sevo-postC group, which was47±4%,45±3%and43±3%respectively (P>0.05). The cTnI level was57.77±4.8ng/ml,58.98±6.09ng/ml and59.74±6.41ng/ml in control group,1.0and2.0MAC sevo-postC group respectively, and there was no difference among three groups (P>0.05). AI was26±2%,28±3%and25±2%in control group,1.0and2.0MAC sevo-postC group respectively, and there was no difference among three groups (P>0.05). Additionally,1.0and2.0MAC sevo-postC failed to enhance the phosphorylation of both Akt and ERK1/2relative to control or sham control group respectively.Interestingly, compared with in young sham control group, the phosphorylation of both Akt and ERK1/2had been increased in old sham control group. The phosphorylated Akt was0.26±0.03arbitrary units and0.45±0.03arbitrary units in young sham control and old sham control group respectively (P<0.05). The phosphorylated ERK1/2was0.23±0.02arbitrary units and0.46±0.03arbitrary units in young sham control and old sham control group (P<0.05). Additional, either1.0or2.0MAC sevo-postC significantly prevented loss of NAD+in young but not old rats compared with control group respectively. The NAD+level was118.57±9.27nmol/g tissue and113.58±9.48nmol/g tissue in1.0and2.0MAC sevo-postC group, which was significantly higer (P<0.05), compared with in control group (46.78±4.54nmol/g tissue) in young rats respectively. The NAD+level was61.15±5.50nmol/g tissue,60.28±7.11nmol/g tissue and58.50±7.16nmol/g tissue in control group,1.0and2.0MAC sevo-postC group in old rats respectively, and there was no difference among three groups. In addition, either1.0or2.0MAC sevo-postC had no effect on the phosphorylation of STAT3in both young and old rats.Conclusion:Sevo-postC significantly reduce IS in young rats in vivo, which could at least be via activation of reperfusion injury salvage kinase (RISK) signaling pathway, thereby inhibition of mPTP opening, but not be via recruitment of JAK2-STAT3signaling cascade. The infarct-limiting effect elicited by sevo-postC in young rats is not effective in old rats, which could be associated with failure to activate Akt, ERK1/2and STAT3signaling and resultant failure to inhibit mPTP opening. |
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