Department of General Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou City, China.
Department of General Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou City, China.
Transplant Proc. 2022 Sep;54(7):2008-2015. doi: 10.1016/j.transproceed.2022.05.025. Epub 2022 Jul 30.
BEZ235, a dual PI3K/mTOR inhibitor, has shown a critical impact in the treatment of cancers, with the ability to induce autophagy. However, the effects of BEZ235 in heart transplant have been rarely investigated. The aim of this study was to evaluate the potency of BEZ235 in cardiac allograft survival.
BEZ235 was administered during the perioperative period of syngeneic or allogeneic heart transplant to assess survival time. Next, the autophagy signaling pathway and the proinflammatory cytokines were analyzed. Furthermore, a cardiomyocytes-specific ATG5 gene-ablated mouse was used to confirm the results.
BEZ235 treatment significantly prolonged the survival of the cardiac graft and reduced the infiltration of inflammatory cells. The expression levels of autophagy proteins were increased in the BEZ235 treatment group compared to the control group, but the therapeutic effect of BEZ235 was weakened in the cardiomyocytes-specific ATG5 gene-ablated mice. Moreover, BEZ235 significantly downregulated the expression of IL-1β, IL-2, and TNF-α.
It seems BEZ235 could induce autophagy and prolonged murine cardiac allograft survival in a mechanism that involved the autophagy pathway and changed multiple inflammatory factors. This study has proposed a theoretical foundation for the strong connection between mTOR-induced autophagy and heart transplant.
BEZ235 是一种双重 PI3K/mTOR 抑制剂，在癌症治疗中具有重要作用，能够诱导自噬。然而，BEZ235 在心脏移植中的作用很少被研究。本研究旨在评估 BEZ235 在心脏移植物存活中的作用。
在同基因或同种异体心脏移植的围手术期给予 BEZ235，以评估存活时间。然后，分析自噬信号通路和促炎细胞因子。此外，还使用心肌细胞特异性 ATG5 基因敲除小鼠来验证结果。
BEZ235 治疗显著延长了心脏移植物的存活时间，并减少了炎症细胞的浸润。与对照组相比，BEZ235 治疗组自噬蛋白的表达水平增加，但在心肌细胞特异性 ATG5 基因敲除小鼠中，BEZ235 的治疗效果减弱。此外，BEZ235 显著下调了 IL-1β、IL-2 和 TNF-α 的表达。
BEZ235 可能通过自噬途径诱导自噬，并改变多种炎症因子，从而延长小鼠心脏移植物的存活时间。这项研究为 mTOR 诱导的自噬与心脏移植之间的紧密联系提供了理论基础。
