Recently the regenerating gene (Reg) has been documented to play an important role in various regenerating tissues, but it is unknown whether Reg gene could be activated in the heart. The aim of this study is to reveal the transcriptional activation of Reg in the heart in response to heart stress. We firstly found REG-1 protein expression in the human hearts obtained from autopsied patients who died of myocardial infarction. REG protein was immunohistochemically stained in a fine granular pattern in the cytoplasm of cardiomyocytes. To demonstrate the activation profiles of Reg gene expression in the heart, we quantified the levels of Reg-1 mRNA in rat hearts after coronary artery ligation, using a real-time RT-PCR. Transient Reg-1 mRNA activation, peaking at 12 h after coronary ligation, was observed mainly in the atria, which was 7-fold higher compared to hearts with pressure-overload due to aortic constriction. In contrast, Reg-receptor mRNA was expressed intensely in damaged ventricles. Furthermore, western blotting showed the corresponding pattern of Reg protein secretion into the serum after loading, and circulating levels of the protein after myocardial infarction were higher than those after aortic constriction. In conclusion, our results demonstrate for the first time the presence of the Reg/Reg-receptor system in damaged hearts. In view of emerging evidence of Reg for tissue regeneration in a variety of tissues/organs, it is proposed that the damaged heart may be a target for Reg action and that Reg may protect against acute heart stress.