Ning Shasha, Guo Xinyue, Zhu Yanan, Li Chenghui, Li Ruixue, Meng Yinan, Luo Weiwei, Lu Dezhang, Yin Yupeng
College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
Military Mental Cognition, Strategic Support Force Medical Center, No. 9 Anxiangbeili, Chaoyang District, Beijing 100101, China.
Int J Biol Macromol. 2024 Aug;275(Pt 1):133514. doi: 10.1016/j.ijbiomac.2024.133514. Epub 2024 Jun 27.
Pulmonary hypertension (PH) is a fatal disease with no existing curative drugs. NF-E2-related factor 2 (NRF2) a pivotal molecular in cellular protection, was investigated in PH models to elucidate its role in regulating abnormal phenotypes in pulmonary artery cells. We examined the expression of NRF2 in PH models and explored the role of NRF2 in regulating abnormal phenotypes in pulmonary artery cells. We determined the expression level of NRF2 in lung tissues of PH model decreased significantly. We found that NRF2 was reduced in rat pulmonary artery endothelial cells (rPAEC) under hypoxia, while it was overexpressed in rat pulmonary artery smooth muscle cells (rPASMC) under hypoxia. Next, the results showed that knockdown NRF2 in rPAEC promoted endothelial-mesenchymal transformation and upregulated reactive oxygen species level. After the rPASMC was treated with siRNA or activator, we found that NRF2 could accelerate cell migration by affecting MMP2/3/7, and promote cell proliferation by regulating PDGFR/ERK1/2 and mTOR/P70S6K pathways. Therefore, the study has shown that the clinical application of NRF2 activator in the treatment of pulmonary hypertension may cause side effects of promoting the proliferation and migration of rPASMC. Attention should be paid to the combination of NRF2 activators.
肺动脉高压（PH）是一种尚无现有治愈药物的致命疾病。核因子E2相关因子2（NRF2）是细胞保护中的关键分子，在PH模型中进行了研究，以阐明其在调节肺动脉细胞异常表型中的作用。我们检测了PH模型中NRF2的表达，并探讨了NRF2在调节肺动脉细胞异常表型中的作用。我们确定PH模型肺组织中NRF2的表达水平显著降低。我们发现，在缺氧条件下大鼠肺动脉内皮细胞（rPAEC）中NRF2减少，而在缺氧条件下大鼠肺动脉平滑肌细胞（rPASMC）中NRF2过表达。接下来，结果表明，敲低rPAEC中的NRF2会促进内皮-间充质转化并上调活性氧水平。在用siRNA或激活剂处理rPASMC后，我们发现NRF2可通过影响MMP2/3/7加速细胞迁移，并通过调节PDGFR/ERK1/2和mTOR/P70S6K途径促进细胞增殖。因此，该研究表明NRF2激活剂在肺动脉高压治疗中的临床应用可能会导致促进rPASMC增殖和迁移的副作用。应注意NRF2激活剂的联合使用。
