Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (3): 650-656.doi: 10.4103/1673-5374.380906

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Astrocytic endothelin-1 overexpression impairs learning and memory ability in ischemic stroke via altered hippocampal neurogenesis and lipid metabolism

Jie Li1, 2, 3, #, Wen Jiang4, #, Yuefang Cai1, #, Zhenqiu Ning1, Yingying Zhou5, Chengyi Wang1, Sookja Ki Chung6, Yan Huang1, 2, 3, Jingbo Sun1, 2, 3, Minzhen Deng1, Lihua Zhou5, Xiao Cheng1, 2, 3, *#br#   

  1. 1Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong Province, China; 2State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China; 3Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, Guangdong Province, China; 4Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China; 5Department of Anatomy, Sun Yat-Sen School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong Province, China; 6Faculty of Medicine, Macau University of Science and Technology, Macao Special Administration Region, China
  • Online:2024-03-15 Published:2023-09-02
  • Contact: Xiao Cheng, MD, PhD, chengxiaolucky@126.com.
  • Supported by:
    This study was financially supported by the National Natural Science Foundation of China, No. 81303115, 81774042 (both to XC); the Pearl River S & T Nova Program of Guangzhou, No. 201806010025 (to XC); the Specialty Program of Guangdong Province Hospital of Chinese Medicine of China, No. YN2018ZD07 (to XC); the Natural Science Foundation of Guangdong Province of China, No. 2023A1515012174 (to JL); the Science and Technology Program of Guangzhou of China, No. 202102010268 (to XC), 202102010339 (to JS); Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Nos. 2018-75, 2019-140 (to JS).

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Abstract: Vascular etiology is the second most prevalent cause of cognitive impairment globally. Endothelin-1, which is produced and secreted by endothelial cells and astrocytes, is implicated in the pathogenesis of stroke. However, the way in which changes in astrocytic endothelin-1 lead to poststroke cognitive deficits following transient middle cerebral artery occlusion is not well understood. Here, using mice in which astrocytic endothelin-1 was overexpressed, we found that the selective overexpression of endothelin-1 by astrocytic cells led to ischemic stroke-related dementia (1 hour of ischemia; 7 days, 28 days, or 3 months of reperfusion). We also revealed that astrocytic endothelin-1 overexpression contributed to the role of neural stem cell proliferation but impaired neurogenesis in the dentate gyrus of the hippocampus after middle cerebral artery occlusion. Comprehensive proteome profiles and western blot analysis confirmed that levels of glial fibrillary acidic protein and peroxiredoxin 6, which were differentially expressed in the brain, were significantly increased in mice with astrocytic endothelin-1 overexpression in comparison with wild-type mice 28 days after ischemic stroke. Moreover, the levels of the enriched differentially expressed proteins were closely related to lipid metabolism, as indicated by Kyoto Encyclopedia of Genes and Genomes pathway analysis. Liquid chromatography-mass spectrometry nontargeted metabolite profiling of brain tissues showed that astrocytic endothelin-1 overexpression altered lipid metabolism products such as glycerol phosphatidylcholine, sphingomyelin, and phosphatidic acid. Overall, this study demonstrates that astrocytic endothelin-1 overexpression can impair hippocampal neurogenesis and that it is correlated with lipid metabolism in poststroke cognitive dysfunction.

Key words: astrocytic endothelin-1, dentate gyrus, differentially expressed proteins, hippocampus, ischemic stroke, learning and memory deficits, lipid metabolism, neural stem cells, neurogenesis, proliferation