Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.

中文翻译：

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Nrf2 对缺血再灌注损伤和心脏同种异体移植物血管病变的保护作用。

缺血再灌注损伤 (IRI) 和心脏同种异体移植物血管病变 (CAV) 仍然是心脏移植 (Tx) 后未解决的并发症。抗氧化转录因子核因子红细胞 2 相关因子 2 (Nrf2) 被认为可以抑制活性氧介导的 NF-κB 激活。我们假设 Nrf2 在 Tx 后抑制 NF-κB 激活并抑制 IRI 和 CAV 的后续发展。IRI 和 CAV 分别在小鼠异位 Tx 模型中进行了研究。Nrf2 野生型 (WT) 和 KO 小鼠用作供体。萝卜硫素用作 Nrf2 激动剂。在同基因移植物再灌注 24 小时后，盐水处理的动物中，与 WT 相比，Nrf2-KO 显示出显着较低的 SOD1/2 活性。Nrf2-KO 显示出显着高的总和磷酸化 p65 表达以及具有核 p65 的细胞百分比。NF-κB 介导的促炎基因的 mRNA 水平也很高。Nrf2-KO 中的移植物功能障碍、细胞凋亡和 caspase-3 活性显着更高。在同种异体移植物研究中，与 WT 相比，Nrf2-KO 的移植物搏动评分明显较弱。Nrf2-KO 还表现出明显更多的冠状动脉管腔狭窄。在 WT 动物中，萝卜硫素通过增加 SOD2 活性成功增强了 Nrf2 的所有保护作用。Nrf2 通过其抗氧化特性抑制 NF-κB 激活并防止 IRI，并抑制 CAV 的后续发展。Nrf2-KO 还表现出明显更多的冠状动脉管腔狭窄。在 WT 动物中，萝卜硫素通过增加 SOD2 活性成功增强了 Nrf2 的所有保护作用。Nrf2 通过其抗氧化特性抑制 NF-κB 激活并防止 IRI，并抑制 CAV 的后续发展。Nrf2-KO 还表现出明显更多的冠状动脉管腔狭窄。在 WT 动物中，萝卜硫素通过增加 SOD2 活性成功增强了 Nrf2 的所有保护作用。Nrf2 通过其抗氧化特性抑制 NF-κB 激活并防止 IRI，并抑制 CAV 的后续发展。