Sequential restoring O2then unloading CO2is beneficial against reperfusion injury: role of CO2in metabolism

Abstract

AbstractCO2is one of main byproducts during mitochondrial oxidation. Under the acute occlusion of coronary artery situation, the intra-tissue pCO2of heart could be extremely high. This CO2accumulation will be acutely unloaded and discharged by blood reperfusion. However, the effect of this intra-tissue CO2accumulation then unloading process on cardiac ischemic reperfusion injury has not been well investigated yet. In the present study, we show that the perfusion with a high level of pCO2and normal pO2in the initial 30min followed by a 30min normal pCO2and normal pO2is better than the perfusion with 1h normal pCO2and normal pO2simultaneously during the reperfusion after a 45min global ischemia in isolated rat hearts. To observe the effect of high pCO2on cellular metabolism, we exposed C2C12 cells under about 370mmHg pCO2to observe the mitochondrial substrate switch and TCA cycle flux change, by using13C tracers. We show that a short time exposure to the extremely high level of pCO2is not completely destructive for cellular metabolism but has specific effects. The high pCO2inhibits pyruvate transport into mitochondria and the next oxidation, switching to more reliance on fatty acid oxidation and enhancing the glutamine oxidation to maintain the TCA cycle. Intriguingly, the high pCO2significantly activates the reductive carboxylation from glutamine, fixation of mitochondrial excessive CO2. The mechanism under the beneficial effect of the high-then-low CO2sequential reperfusion strategy is discussed further.