Positive feedback induced memory effect in ischemic preconditioning

The memory of ischemic preconditioning remains a great mystery. Brief preconditioning (several sequential regional ischemia/reperfusion in minutes) can induce a two-phase protection that lasts up to 3 days. Thus comes the so-called memory of preconditioning. This memory effect has been attributed to a feed-forward signaling cascade. But recent experimental observations suggest that intra-mitochondrial positive feedback may be responsible for sustaining the protective effect. The link between positive feedback and memory is yet to be determined. In this study, we used a mathematical model to describe the way in which positive feedback induces memory in the first window of cardioprotection, and we derived an explicit relationship between the memory duration and the strength of the positive feedback. Our major findings are: (1) that positive feedback relying on a hysteresis response provides an effective way of prolonging protection up to any length; and (2) that the stronger the positive feedback, the longer the memory duration. Furthermore, compared with the feed-forward signaling cascade, positive feedback may be more favored by natural systems because of its robustness and high efficiency. The mechanisms described in this study have important implications for developments of experimental approaches as well as therapeutic strategies.