Department of Pulmonary and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, People's Republic of China.
Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
Respir Res. 2024 May 10;25(1):205. doi: 10.1186/s12931-024-02827-w.
Obesity is the main risk factor leading to the development of various respiratory diseases, such as asthma and pulmonary hypertension. Pulmonary microvascular endothelial cells (PMVECs) play a significant role in the development of lung diseases. Aconitate decarboxylase 1 (Acod1) mediates the production of itaconate, and Acod1/itaconate axis has been reported to play a protective role in multiple diseases. However, the roles of Acod1/itaconate axis in the PMVECs of obese mice are still unclear.
mRNA-seq was performed to identify the differentially expressed genes (DEGs) between high-fat diet (HFD)-induced PMVECs and chow-fed PMVECs in mice (|log fold change| ≥ 1, p ≤ 0.05). Free fatty acid (FFA) was used to induce cell injury, inflammation and mitochondrial oxidative stress in mouse PMVECs after transfection with the Acod1 overexpressed plasmid or 4-Octyl Itaconate (4-OI) administration. In addition, we investigated whether the nuclear factor erythroid 2-like 2 (Nrf2) pathway was involved in the effects of Acod1/itaconate in FFA-induced PMVECs.
Down-regulated Acod1 was identified in HFD mouse PMVECs by mRNA-seq. Acod1 expression was also reduced in FFA-treated PMVECs. Acod1 overexpression inhibited cell injury, inflammation and mitochondrial oxidative stress induced by FFA in mouse PMVECs. 4-OI administration showed the consistent results in FFA-treated mouse PMVECs. Moreover, silencing Nrf2 reversed the effects of Acod1 overexpression and 4-OI administration in FFA-treated PMVECs, indicating that Nrf2 activation was required for the protective effects of Acod1/itaconate.
Our results demonstrated that Acod1/Itaconate axis might protect mouse PMVECs from FFA-induced injury, inflammation and mitochondrial oxidative stress via activating Nrf2 pathway. It was meaningful for the treatment of obesity-caused pulmonary microvascular endotheliopathy.
肥胖是导致各种呼吸系统疾病发展的主要危险因素，如哮喘和肺动脉高压。肺微血管内皮细胞（PMVECs）在肺部疾病的发展中起着重要作用。顺乌头酸酶 1（Acod1）介导异丁烯酸的产生，并且 Acod1/异丁烯酸轴已被报道在多种疾病中发挥保护作用。然而，Acod1/异丁烯酸轴在肥胖小鼠 PMVECs 中的作用尚不清楚。
通过 mRNA-seq 鉴定高脂肪饮食（HFD）诱导的 PMVECs 和小鼠 Chow 喂养的 PMVECs 之间差异表达基因（DEGs）（|log fold change|≥1，p≤0.05）。在用 Acod1 过表达质粒转染或给予 4-辛基异丁烯酸（4-OI）后，用游离脂肪酸（FFA）诱导小鼠 PMVECs 细胞损伤、炎症和线粒体氧化应激。此外，我们还研究了核因子红细胞 2 样 2（Nrf2）通路是否参与了 Acod1/异丁烯酸在 FFA 诱导的 PMVECs 中的作用。
通过 mRNA-seq 鉴定出 HFD 小鼠 PMVECs 中下调的 Acod1。FFA 处理的 PMVECs 中 Acod1 的表达也降低。Acod1 过表达抑制了 FFA 诱导的小鼠 PMVECs 中的细胞损伤、炎症和线粒体氧化应激。4-OI 给药在 FFA 处理的小鼠 PMVECs 中显示出一致的结果。此外，沉默 Nrf2 逆转了 FFA 处理的 PMVECs 中转录激活因子 1 过表达和 4-OI 给药的作用，表明 Nrf2 激活是 Acod1/异丁烯酸保护作用所必需的。
我们的结果表明，Acod1/异丁烯酸轴可能通过激活 Nrf2 通路来保护小鼠 PMVECs 免受 FFA 诱导的损伤、炎症和线粒体氧化应激。这对于治疗肥胖引起的肺微血管内皮病变具有重要意义。
Zotero 插件
