Recently, the regenerating gene ( Reg) has been documented to play an important role in various regenerating tissues, but it is unknown whether the Reg gene could be activated in the heart. The aim of this study was to reveal the transcriptional activation of Reg in the heart in response to heart stress. We first found REG-1 protein expression in 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 real-time RT-PCR. Transient Reg-1 mRNA activation, peaking at 12 h after coronary ligation, was observed mainly in the atria, which was sevenfold higher compared with hearts with pressure overload due to aortic constriction. In contrast, Reg receptor mRNA was expressed intensely in damaged ventricles. Furthermore, Western blot analysis 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.

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The regenerative capacity of viable cells remaining in cryopreserved vascular allografts is still unclear. Recently, the regenerating gene (Reg) has been documented to play an important role in various regenerating tissues. Here we show the possibility of Reg induction for the enhancement of cryopreserved vascular allograft viability. Cryopreserved rat aortae were isografted or allografted heterotopically. Fresh isografts were also tested. The transplants were retrieved 3, 6, 9, and 12 days after implantation and the intragraft Reg mRNA was measured by a real-time quantitative reverse transcriptional polymerase chain reaction method. Reg expression was not detected before implantation. Reg expression in cryopreserved isografts gradually increased after transplantation, whereas in fresh isografts or cryopreserved allografts it decreased over time after initial expression. Daily administration of 0.5 g/kg nicotinamide (an agent known to be a potent inducer of Reg) induced intragraft Reg mRNA in cryopreserved allografts (p < 0.05) accompanied by augmentation of the intragraft cell population. Daily administration of 0.5 mg/kg FK506 (an immunosuppressant) induced intragraft Reg mRNA both in cryopreserved isografts and allografts (p < 0.01). We conclude that Reg-inductive therapy shows promise as a novel strategy for enhancing the viability of vascular allografts. Moreover, FK506 may be involved in tissue regeneration as well as immunosuppression.

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