乙酰化亲环素A是缺氧诱导的自噬和肺血管生成的主要介质。
Acetylated cyclophilin A is a major mediator in hypoxia-induced autophagy and pulmonary vascular angiogenesis.
作者信息
Mao Min, Yu Xiufeng, Ge Xin, Gu Rui, Li Qian, Song Shasha, Zheng Xiaodong, Shen Tingting, Li Xuecang, Fu Yao, Li Jiali, Zhu Daling
机构信息
aDepartment of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Daqing bBiopharmaceutical Key Laboratory of Heilongjiang Province, Harbin cDepartment of Pharmaceutical Analysis, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province dDepartment of Pathophysiology, College of Basic Medicine, Harbin Medical University, Daqing, China.
出版信息
J Hypertens. 2017 Apr;35(4):798-809. doi: 10.1097/HJH.0000000000001224.
BACKGROUND
Autophagy is a major intracellular degradation and recycling process that maintains cellular homeostasis, which is involved in structural and functional abnormalities of pulmonary vasculature in hypoxic pulmonary arterial hypertension (HPAH). Cyclophilin A (CyPA) is a secreted, oxidative stress-induced factor. Its role in inducing autophagy and augmenting endothelial cell dysfunction has never been explored.
METHODS
Lungs from rats exposed to chronic hypoxia were examined for autophagy with electron microscopy, western blotting, and fluorescence microscopy.
RESULTS
Activated autophagy was seen in the endothelium of the pulmonary artery from experimental rat models of HPAH and cultured bovine pulmonary arterial endothelial cells under hypoxia. Inhibiting autophagy attenuated the pathological progression of HPAH and repressed endothelial cell migration and angiogenesis. We also showed that CyPA was upregulated and acetylated under hypoxia and led to the abnormal occurrence of autophagy through its interaction with autophagy protein 5 and autophagy protein 7. Moreover, acetylated CyPA was essential for the excessive proliferation, migration, and tube formation networks of pulmonary arterial endothelial cells.
CONCLUSION
Our results indicate the crucial role of acetylated CyPA in the abnormal occurrence of autophagy and subsequent pulmonary vascular angiogenesis.
背景
自噬是一种主要的细胞内降解和再循环过程，可维持细胞稳态，其参与了低氧性肺动脉高压（HPAH）中肺血管的结构和功能异常。亲环素A（CyPA）是一种分泌型的、氧化应激诱导因子。其在诱导自噬和加剧内皮细胞功能障碍方面的作用从未被探究过。
方法
用电子显微镜、蛋白质免疫印迹法和荧光显微镜检查暴露于慢性低氧环境的大鼠的肺组织中的自噬情况。
结果
在HPAH实验大鼠模型的肺动脉内皮以及低氧条件下培养的牛肺动脉内皮细胞中均可见自噬激活。抑制自噬可减轻HPAH的病理进展，并抑制内皮细胞迁移和血管生成。我们还发现，低氧条件下CyPA表达上调并发生乙酰化，且通过与自噬蛋白5和自噬蛋白7相互作用导致自噬异常发生。此外，乙酰化的CyPA对于肺动脉内皮细胞的过度增殖、迁移及形成管腔网络至关重要。
结论
我们的结果表明乙酰化的CyPA在自噬异常发生及随后的肺血管生成中起关键作用。
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