FKBP prolyl isomerase 4: a potential target for heart failure and cardioprotective effects via leonurine-pretreated mesenchymal stem cell-derived exosomes

Background: The use of mesenchymal stem cell-derived exosomes (MSC-EXOs) is a promising strategy for treating heart failure. Pretreatment of MSCs with cardioprotective agents, such as leonurine, has the potential to augment the therapeutic efficacy of their EXO activities. However, the cardioprotective potential of EXOs derived from MSCs pretreated with leonurine (MSCLeo-EXO) remains unexplored. Methods: MSCLeo-EXO were isolated following a 48-hour culture period of the MSCs in a leonurine-supplemented medium. The cardioprotective effects of MSCLeo-EXOs were investigated both in vitro and in vivo via a hypoxia-induced cardiomyocyte injury model, a TGF-β-induced cardiomyocyte fibrosis model, and a mouse model of heart failure. Additionally, the compositions of the MSCLeo-EXOs and control EXOs were compared via miRNA sequencing. Experiments using loss-of-function and overexpression methods were carried out to learn more about the precise processes that underlie the action of MSCLeo-EXOs. Results: MSCLeo-EXO were successfully isolated and possessed the characteristics of EXOs. Compared with EXOs from untreated MSCs, those from MSCLeo-EXOs inhibited pyroptosis, protected cardiomyocytes from hypoxia-induced apoptosis damage, enhanced cardiac function, and reduced fibrosis and collagen deposition in heart failure model mice. Furthermore, miRNA sequencing revealed that MSCLeo-EXOs contained a greater level of miR-3152-5p. Both in vivo and in vitro, the cardioprotective effects mediated by MSCLeo-EXOs were diminished by miR-3152-5p knockdown. Increased miR-3152-5p mechanistically enhanced the cardioprotective effect of MSCLeo-EXOs by targeting and inhibiting the expression of FKBP prolyl isomerase 4 (FKBP4), reducing fibrosis and inflammatory responses, and mitigating hypoxia-induced cell damage. Conclusion: Our findings revealed that pretreatment of MSCs with leonurine increased miR-3152-5p expression in EXOs, which enhanced the cardioprotective effect of MSCLeo-EXOs. In addition, our study is the first to reveal the pivotal role of FKBP4 in heart failure, providing novel insights into the therapeutic potential of exosome-based interventions for this condition.