小脑素-2通过激活NF-κB/HIF-1α/Twist1信号通路促进低氧性肺动脉高压大鼠的内皮-间充质转化。
Cerebellin-2 promotes endothelial-mesenchymal transition in hypoxic pulmonary hypertension rats by activating NF-κB/HIF-1α/Twist1 pathway.
作者信息
Wang E-Li, Zhang Jie-Jie, Luo Fang-Mei, Fu Min-Yi, Li Dai, Peng Jun, Liu Bin
机构信息
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
Department of Obstetrics, Xiangya Hospital, Central South University, Changsha 410008, China.
出版信息
Life Sci. 2023 Sep 1;328:121879. doi: 10.1016/j.lfs.2023.121879. Epub 2023 Jun 22.
AIMS
Endothelial-mesenchymal transition (EndMT) is one of the critical factors leading to vascular remodeling in pulmonary hypertension (PH). Recent studies found that the expression of Cerebellin-2 (CBLN2) is significantly increased in the lung tissue of patients with PH, suggesting that CBLN2 may be closely related to the development of PH. This study aims to investigate the role and potential mechanism of CBLN2 in the hypoxia-induced EndMT of PH rats.
MATERIAL AND METHODS
Hypoxia-induced PH rat model or EndMT cell model was constructed to investigate the role of CBLN2 in the process of endothelial mesenchymal transition during PH. The effects of CBLN2 siRNA, KC7F2 (HIF-1α inhibitor), and PDTC (NF-κB inhibitor) on hypoxia-induced EndMT were observed to evaluate the potential mechanism of CBLN2 in promoting EndMT.
KEY FINDINGS
The right ventricular systolic pressure and pulmonary vascular remodeling index in hypoxia-treated rats were significantly increased. The transformation of endothelial cells (marked by CD31) to mesenchymal cells (marked by α-SMA) can be observed in the pulmonary vessels of PH rats, and the expression of CBLN2 in the intima was also significantly up-regulated. In the hypoxia-induced HPAECs, endothelial cell markers such as VE-cadherin and CD31 expression were significantly down-regulated, while mesenchymal-like cell markers such as α-SMA and vimentin were increased considerably, along with the increased expressions of CBLN2, p-p65, HIF-1α, and Twist1; CBLN2 siRNA, PDTC, and KC7F2 could inhibit those phenomena.
SIGNIFICANCE
CBLN2 can promote EndMT by activating NF-κB/HIF-1α/Twist1 pathway. Therefore, CBLN2 may be a new therapeutic target for PH.
目的
内皮-间充质转化（EndMT）是导致肺动脉高压（PH）血管重塑的关键因素之一。最近的研究发现，小脑素-2（CBLN2）在PH患者的肺组织中表达显著增加，提示CBLN2可能与PH的发生发展密切相关。本研究旨在探讨CBLN2在低氧诱导的PH大鼠EndMT中的作用及潜在机制。
材料与方法
构建低氧诱导的PH大鼠模型或EndMT细胞模型，以研究CBLN2在PH内皮间充质转化过程中的作用。观察CBLN2小干扰RNA（siRNA）、KC7F2（HIF-1α抑制剂）和PDTC（NF-κB抑制剂）对低氧诱导的EndMT的影响，以评估CBLN2促进EndMT的潜在机制。
主要发现
低氧处理大鼠的右心室收缩压和肺血管重塑指数显著升高。在PH大鼠的肺血管中可观察到内皮细胞（以CD31标记）向间充质细胞（以α-SMA标记）的转化，且内膜中CBLN2的表达也显著上调。在低氧诱导的人肺动脉内皮细胞（HPAECs）中，内皮细胞标志物如血管内皮钙黏蛋白（VE-cadherin）和CD31的表达显著下调，而间充质样细胞标志物如α-SMA和波形蛋白显著增加，同时CBLN2、磷酸化p65（p-p65）、HIF-1α和Twist1的表达也增加；CBLN2 siRNA、PDTC和KC7F2可抑制这些现象。
意义
CBLN2可通过激活NF-κB/HIF-1α/Twist1通路促进EndMT。因此，CBLN2可能是PH的一个新的治疗靶点。
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