In this study, we were pleasantly surprised to observe that SCU treatment can significantly restored CTSD protein levels and increased its enzyme activity and found that the inhibition of CTSD almost completely abrogated the protective effects of SCU in I/R injury both in vivo and in vitro, suggesting that CTSD is essential for SCU in antagonizing I/R-mediated endothelial dysfunction and cardiac I/R injury. This evidence concerns the gene CTSD and endothelial dysfunction.