Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice.
Protein Phosphatase 2A Activation Promotes Heart Transplant Acceptance in Mice.
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DOI：
10.1097/tp.0000000000004832
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发表时间：
2023-10
期刊：
影响因子：
6.2
通讯作者：
Xianming Zhou;Qian Xu;Wangzi Li;Nianguo Dong;Colin Stomberski;G. Narla;Zhiyong Lin
中科院分区：
文献类型：
--
作者：
Xianming Zhou;Qian Xu;Wangzi Li;Nianguo Dong;Colin Stomberski;G. Narla;Zhiyong Lin
背景。尽管心脏移植是符合条件的患者心力衰竭的最终治疗方法，但急性和慢性移植排斥反应经常发生。蛋白磷酸酶 2A (PP2A) 活性对于维持组织和器官稳态至关重要。在这项研究中，我们评估了一类新型 PP2A 小分子激活剂 (SMAP) 对小鼠异位心脏移植模型中同种异体移植排斥的影响。方法。移植后第 1 天开始，通过口服强饲法向受体小鼠施用 DT-061（一种药物优化的 SMAP）或载体。进行组织学和免疫荧光分析以检查同种异体移植排斥。对来自受体脾脏的调节性 T 细胞 (Treg) 进行流式细胞术和 RNA 测序分析。最后，评估了 DT-061 对平滑肌细胞 (SMC) 迁移和增殖的影响。结果。 DT-061 治疗可延长同种异体心脏移植物的存活率。 SMAP 有效抑制炎症免疫反应，同时增加同种异体移植物中的 Treg 数量，对处理过的脾组织 Treg 的 RNA 测序数据进行功能分析证实了这一发现。重要的是，SMAP 延长了免疫抑制剂细胞毒性 T 淋巴细胞相关抗原 4-Ig 诱导的心脏移植耐受性和同种异体移植物的存活率。 SMAP 还可以显着减轻心脏同种异体移植血管病变，新内膜增生和 SMC 增殖的显着减少就证明了这一点。最后，我们的体外研究表明 MEK/ERK 通路的抑制是 Treg 和 SMC 中 PP2A 调节作用的统一机制。结论。在小鼠模型中，PP2A 激活可防止心脏排斥并延长同种异体移植物的存活时间。我们的研究结果强调了 PP2A 激活在改善心脏移植同种异体移植方面的潜力。
Background. Although heart transplantation is the definitive treatment for heart failure in eligible patients, both acute and chronic transplant rejection frequently occur. Protein phosphatase 2A (PP2A) activity is critical in maintaining tissue and organ homeostasis. In this study, we evaluated the effect of a novel class of small molecule activators of PP2A (SMAPs) on allograft rejection in a mouse heterotopic heart transplantation model. Methods. Recipient mice were administered with DT-061 (a pharmaceutically optimized SMAP) or vehicle by oral gavage beginning 1 d after transplantation. Histological and immunofluorescence analyses were performed to examine allograft rejection. Regulatory T cells (Treg) from recipient spleens were subjected to flow cytometry and RNA sequencing analysis. Finally, the effect of DT-061 on smooth muscle cells (SMCs) migration and proliferation was assessed. Results. DT-061 treatment prolonged cardiac allograft survival. SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNA sequencing data derived from Treg of treated splenic tissues. Importantly, SMAPs extended immunosuppressive agent cytotoxic T lymphocyte–associated antigen-4-Ig–induced cardiac transplantation tolerance and allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and SMC proliferation. Finally, our in vitro studies implicate suppression of MEK/ERK pathways as a unifying mechanism for the effect of PP2A modulation in Treg and SMCs. Conclusions. PP2A activation prevents cardiac rejection and prolongs allograft survival in a murine model. Our findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation.