In this report, we have identified Nrg1β as a RIPC factor and provide evidence that RIPC induced Nrg1β is secreted by microvascular endothelial cells of gastrocnemius muscle, which interacts with endothelial ErbB2 preventing its degradation in I/R resulting in inhibitory phosphorylation of ATG5 and consequent protection of Trx2 degradation in IR providing a significant protection against MI. Here, ATG5 is linked to myocardial infarction.