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Abstract：
BACKGROUND: 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.
METHODS: mRNA-seq was performed to identify the differentially expressed genes (DEGs) between high-fat diet (HFD)-induced PMVECs and chow-fed PMVECs in mice (|log2 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: mRNA-seq was performed to identify the differentially expressed genes (DEGs) between high-fat diet (HFD)-induced PMVECs and chow-fed PMVECs in mice (|log2 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：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）在肺部疾病的发生发展中起着重要作用。乌头酸脱羧酶1（Acod1）介导衣康酸的生产，据报道，Acod1/衣康酸轴在多种疾病中起保护作用。然而,Acod1/衣康酸轴在肥胖小鼠PMVECs中的作用尚不清楚.
方法：进行mRNA-seq以鉴定高脂饮食（HFD）诱导的小鼠PMVECs和食物喂养的PMVECs之间的差异表达基因（DEGs）（|log2倍数变化|≥1，p≤0.05）。游离脂肪酸(FFA)用于诱导细胞损伤,用Acod1过表达的质粒或4-辛基衣酯（4-OI）给药后，小鼠PMVEC中的炎症和线粒体氧化应激。此外,我们研究了核因子类红细胞2样2(Nrf2)通路是否参与了Acod1/衣康酸在FFA诱导的PMVECs中的作用.
结果:通过mRNA-seq在HFD小鼠PMVEC中鉴定出下调的Acod1。在FFA处理的PMVEC中Acod1表达也降低。Acod1过表达抑制细胞损伤，FFA诱导的小鼠PMVECs炎症和线粒体氧化应激。4-OI施用在FFA处理的小鼠PMVEC中显示一致的结果。此外，沉默Nrf2逆转了FFA处理的PMVECs中Acod1过表达和4-OI给药的效果，表明Nrf2激活是Acod1/衣康酸的保护作用所必需的。
结论：我们的结果表明，Acod1/衣酯轴可能保护小鼠PMVECs免受FFA诱导的损伤，炎症和线粒体氧化应激经由过程激活Nrf2通路。这对肥胖引起的肺微血管内皮病的治疗具有重要意义。
方法：进行mRNA-seq以鉴定高脂饮食（HFD）诱导的小鼠PMVECs和食物喂养的PMVECs之间的差异表达基因（DEGs）（|log2倍数变化|≥1，p≤0.05）。游离脂肪酸(FFA)用于诱导细胞损伤,用Acod1过表达的质粒或4-辛基衣酯（4-OI）给药后，小鼠PMVEC中的炎症和线粒体氧化应激。此外,我们研究了核因子类红细胞2样2(Nrf2)通路是否参与了Acod1/衣康酸在FFA诱导的PMVECs中的作用.
结果:通过mRNA-seq在HFD小鼠PMVEC中鉴定出下调的Acod1。在FFA处理的PMVEC中Acod1表达也降低。Acod1过表达抑制细胞损伤，FFA诱导的小鼠PMVECs炎症和线粒体氧化应激。4-OI施用在FFA处理的小鼠PMVEC中显示一致的结果。此外，沉默Nrf2逆转了FFA处理的PMVECs中Acod1过表达和4-OI给药的效果，表明Nrf2激活是Acod1/衣康酸的保护作用所必需的。
结论：我们的结果表明，Acod1/衣酯轴可能保护小鼠PMVECs免受FFA诱导的损伤，炎症和线粒体氧化应激经由过程激活Nrf2通路。这对肥胖引起的肺微血管内皮病的治疗具有重要意义。
