Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Oxid Med Cell Longev. 2022 Jul 9;2022:7260305. doi: 10.1155/2022/7260305. eCollection 2022.
Despite being the gold-standard treatment for end-stage heart disease, heart transplantation is associated with acute cardiac rejection within 1 year of transplantation. The continuous application of immunosuppressants may cause side effects such as hepatic and renal toxicity, infection, and malignancy. Developing new pharmaceutical strategies to alleviate acute rejection after heart transplantation effectively and safely is of critical importance. In this study, we performed a murine model of MHC-full mismatch cardiac transplantation and showed that the combination of Rhodosin (Rho) and mycophenolate mofetil (MMF) could prevent acute rejection and oxidative stress injury and prolong the survival time of murine heart transplants. The use of Rho plus MMF in allografts improved the balance of Tregs/Teff cells, which had a protective effect on allotransplantation. We also isolated bone marrow-derived dendritic cells (BMDCs) and determined that Rho inhibited DC maturation by promoting mitochondrial fusion mainly through the mitochondrial fusion-related protein MFN1. Herein, we demonstrated that Rho, an active ingredient isolated from the plant with antioxidant and anti-inflammatory activities, could efficiently alleviate acute rejection and significantly prolong murine heart allograft survival when used with a low dose of MMF. More importantly, we found that Rho restrained DC maturation by promoting mitochondrial fusion and decreasing reactive oxygen species (ROS) levels, which then alleviated acute rejection in murine cardiac transplantation. Interestingly, as a novel immunosuppressant, Rho has almost no side effects compared with other traditional immunosuppressants. Taken together, these results suggest that Rho has good clinical auxiliary applications as an effective immunosuppressant and antioxidant, and this study provides an efficient strategy to overcome the side effects of immunosuppressive agents that are currently used in organ transplantation.
尽管心脏移植是治疗终末期心脏病的金标准，但在移植后 1 年内仍会发生急性心脏排斥反应。持续应用免疫抑制剂可能会导致肝肾功能毒性、感染和恶性肿瘤等副作用。开发新的药物策略，有效且安全地缓解心脏移植后的急性排斥反应至关重要。在这项研究中，我们建立了 MHC 完全不匹配的小鼠心脏移植模型，并表明罗红霉素（Rho）和霉酚酸酯（MMF）联合应用可以预防急性排斥反应和氧化应激损伤，延长小鼠心脏移植的存活时间。在同种异体移植物中使用 Rho 加 MMF 可改善 Tregs/Teff 细胞的平衡，对同种异体移植具有保护作用。我们还分离了骨髓来源的树突状细胞（BMDC），并确定 Rho 通过促进线粒体融合主要通过线粒体融合相关蛋白 MFN1 抑制 DC 成熟。在此，我们证明了 Rho，一种具有抗氧化和抗炎活性的植物中的活性成分，与低剂量 MMF 联合使用时，可有效缓解急性排斥反应，并显著延长小鼠心脏同种异体移植物的存活时间。更重要的是，我们发现 Rho 通过促进线粒体融合和降低活性氧（ROS）水平来抑制 DC 成熟，从而减轻小鼠心脏移植中的急性排斥反应。有趣的是，作为一种新型免疫抑制剂，与其他传统免疫抑制剂相比，Rho 的副作用几乎可以忽略不计。总之，这些结果表明 Rho 作为一种有效的免疫抑制剂和抗氧化剂具有良好的临床辅助应用前景，该研究为克服目前用于器官移植的免疫抑制剂的副作用提供了一种有效的策略。
