Modulation of cardiac sarcoplasmic reticulum gene expression by lack of oxygen and glucose

Although ischemia reperfusion has been shown to depress gene expression of the sarcoplasmic reticulum (SR) proteins, such as the ryanodine receptor, Ca2+-pump ATPase, phospholamban, and calsequestrin in the heart, the mechanisms of these changes are not understood. Given the occurrence of hypoxia and the lack of glucose during the ischemic phase, we investigated the effects of these factors on the cardiac SR gene expression. Isolated rat hearts perfused in the absence of oxygen and/or glucose for 30 min showed an increase in the expression of SR genes. However, perfusion of hearts for 60 min with normal oxygenated medium after 30 min of lack of both oxygen and glucose depressed the transcript levels for the SR proteins; these changes did not occur when hearts were deprived of either oxygen or glucose. The effect of intracellular Ca2+-overload, which occurs during reperfusion, was studied by using hearts perfused for 5 min with Ca2+-free medium and then reperfused for 30 min. Ca2+-depletion/repletion induced a dramatic decrease in the transcript levels of the SR genes. These results suggest that the lack of both oxygen and glucose during ischemia are necessary for reperfusion-induced depression in SR gene expression, possibly due to the occurrence of intracellular Ca2+-overload.