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Endothelial Conditional Knockdown of NMMHC IIA (Nonmuscle Myosin Heavy Chain IIA) Attenuates Blood-Brain Barrier Damage During Ischemia-Reperfusion Injury.
Gong, Shuaishuai; Cao, Guosheng; Li, Fang; Chen, Zhuo; Pan, Xuewei; Ma, Huifen; Zhang, Yuanyuan; Yu, Boyang; Kou, Junping.
  • Gong S; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
  • Cao G; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
  • Li F; College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, PR China (G.C.).
  • Chen Z; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
  • Pan X; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
  • Ma H; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
  • Zhang Y; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
  • Yu B; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
  • Kou J; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, PR China (S.G., G.C., F.L., Z.C., X.P., H.M., Y.Z., B.Y.,
Stroke ; 52(3): 1053-1064, 2021 03.
Article en En | MEDLINE | ID: mdl-33588591
BACKGROUND AND PURPOSE: In ischemic stroke, breakdown of the blood-brain barrier (BBB) aggravates brain damage. Endothelial detachment contributes to BBB disruption and neurovascular dysfunction, but its regulation in stroke has yet to be clarified. We investigated the function of NMMHC IIA (nonmuscle myosin heavy chain IIA) in the endothelium on BBB breakdown and its potential mechanisms. METHODS: Endothelial conditional knockdown NMMHC IIA (Myh9ECKD) was constructed in vivo and in vitro, and its role was explored in middle cerebral artery occlusion/reperfusion-injured mice and oxygen-glucose deprivation/reoxygenation-injured brain microvascular endothelial cells. The degree of brain injury was analyzed using staining (2,3,5-triphenyltetrazolium chloride, hematoxylin, and eosin) and electron microscopy. BBB breakdown was investigated with leakage of Evans Blue dye and expression of TJs (tight junctions) and MMP (matrix metallopeptidase)-2/9. Transcriptomics for enrichment analysis was adopted to explore the potential downstream signaling pathways of NMMHC IIA involved in middle cerebral artery occlusion/reperfusion-induced BBB dysfunction. RESULTS: NMMHC IIA expression was upregulated in endothelial cells after cerebral ischemia/reperfusion injury. Myh9ECKD mice exhibited improvement in endothelial barrier hyperpermeability and TJs integrity stimulated by cerebral ischemia/reperfusion. Blebbistatin (NMMHC II inhibitor) treatment exerted the same effect. Transcriptomics showed that NMMHC IIA was involved in regulating various BBB-related genomic changes in the middle cerebral artery occlusion/reperfusion model, and NMMHC IIA was confirmed to significantly modulate Hippo and peroxisome proliferator-activated receptor gamma/nuclear factor-kappa B signaling pathways, which are closely related to BBB damage. CONCLUSIONS: Our findings provide some new insights into how NMMHC IIA contributes to maintaining the integrity of the cerebral endothelial barrier. NMMHC IIA could be a potential therapeutic target for ischemic stroke.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Daño por Reperfusión / Isquemia Encefálica / Cadenas Pesadas de Miosina / Infarto de la Arteria Cerebral Media / Células Endoteliales Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2021 Tipo del documento: Article
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Daño por Reperfusión / Isquemia Encefálica / Cadenas Pesadas de Miosina / Infarto de la Arteria Cerebral Media / Células Endoteliales Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2021 Tipo del documento: Article