β-aminoisobutyrics acid, a metabolite of BCAA, activates the AMPK/Nrf-2 pathway to prevent ferroptosis and ameliorates lung ischemia-reperfusion injury.
β-aminoisobutyrics acid, a metabolite of BCAA, activates the AMPK/Nrf-2 pathway to prevent ferroptosis and ameliorates lung ischemia-reperfusion injury.
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DOI：
10.1186/s10020-023-00729-z
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发表时间：
2023-12-04
期刊：
影响因子：
--
通讯作者：
Zeng C
中科院分区：
文献类型：
--
作者：
Zhang Z;Li X;Guo J;He B;Wu L;Yang R;Li X;Fang D;Yang X;Yang D;Wang F;Tang M;Han Y;Jose PA;Wang H;Zeng C
肺缺血再灌注损伤是一个严重的临床问题，目前尚无有效的治疗方法。增强支链氨基酸（BCAA）代谢可保护心肌免受I/R损伤，这可能与BCAA代谢产物产生的生物活性分子有关。BCAA的代谢产物L-β-氨基异丁酸（L-BAIBA）具有多器官保护作用，但其是否能保护肺I/R损伤尚不清楚。为了评估L-BAIBA对肺I/R损伤的保护作用，通过在C57BL/6小鼠中夹闭左肺门，然后释放夹来产生动物模型。用L-BAIBA（150 mg/kg/d）对肺I/R损伤的小鼠进行预处理或后处理，通过管饲或腹腔注射给予。通过测量肺水肿和分析血气来评估肺损伤。通过测量支气管肺泡灌洗液（BALF）中的促炎细胞因子来评估炎症，并通过髓过氧化物酶活性来测量肺的中性粒细胞浸润。采用分子生物学方法，包括免疫印迹和免疫荧光检测A549和BEAS-2B细胞中潜在的信号转导机制。我们发现L-BAIBA对C57 BL/6小鼠肺I/R损伤有保护作用，其机制可能与上调GPX4和SLC7A11的表达有关。此外，我们证明了Nrf-2信号通路是L-BAIBA对A549和BEAS-2B细胞中的铁凋亡的抑制作用的关键。L-BAIBA可诱导Nrf-2核转位。干扰Nrf-2的表达可消除L-BAIBA对铁凋亡的保护作用。对L-BAIBA诱导的Nrf-2核转位信号通路的筛选结果表明，L-BAIBA能增加AMPK的磷酸化，化合物C能阻断L-BAIBA诱导的Nrf-2核转位。化合物C的存在也阻断了L-BAIBA对C57BL/6小鼠肺I/R损伤的保护作用。我们的研究表明，L-BAIBA通过AMPK/Nrf-2信号通路保护肺I/R损伤，这可能是一个治疗靶点。在线版本包含补充材料，可通过10.1186/s10020 - 023 - 00729-z获得。
Lung ischemia-reperfusion (I/R) injury is a serious clinical problem without effective treatment. Enhancing branched-chain amino acids (BCAA) metabolism can protect against cardiac I/R injury, which may be related to bioactive molecules generated by BCAA metabolites. L-β-aminoisobutyric acid (L-BAIBA), a metabolite of BCAA, has multi-organ protective effects, but whether it protects against lung I/R injury is unclear. To assess the protective effect of L-BAIBA against lung I/R injury, an animal model was generated by clamping the hilum of the left lung, followed by releasing the clamp in C57BL/6 mice. Mice with lung I/R injury were pre-treated or post-treated with L-BAIBA (150 mg/kg/day), given by gavage or intraperitoneal injection. Lung injury was assessed by measuring lung edema and analyzing blood gases. Inflammation was assessed by measuring proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), and neutrophil infiltration of the lung was measured by myeloperoxidase activity. Molecular biological methods, including western blot and immunofluorescence, were used to detect potential signaling mechanisms in A549 and BEAS-2B cells. We found that L-BAIBA can protect the lung from I/R injury by inhibiting ferroptosis, which depends on the up-regulation of the expressions of GPX4 and SLC7A11 in C57BL/6 mice. Additionally, we demonstrated that the Nrf-2 signaling pathway is key to the inhibitory effect of L-BAIBA on ferroptosis in A549 and BEAS-2B cells. L-BAIBA can induce the nuclear translocation of Nrf-2. Interfering with the expression of Nrf-2 eliminated the protective effect of L-BAIBA on ferroptosis. A screening of potential signaling pathways revealed that L-BAIBA can increase the phosphorylation of AMPK, and compound C can block the Nrf-2 nuclear translocation induced by L-BAIBA. The presence of compound C also blocked the protective effects of L-BAIBA on lung I/R injury in C57BL/6 mice. Our study showed that L-BAIBA protects against lung I/R injury via the AMPK/Nrf-2 signaling pathway, which could be a therapeutic target. The online version contains supplementary material available at 10.1186/s10020-023-00729-z.
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影响因子：
5
作者：
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