1. Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage.
- Author
-
Feng D, Zhou J, Liu H, Wu X, Li F, Zhao J, Zhang Y, Wang L, Chao M, Wang Q, Qin H, Ge S, Liu Q, Zhang J, and Qu Y
- Subjects
- Animals, Astrocytes metabolism, Blood-Brain Barrier metabolism, Disease Models, Animal, Humans, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Matrix Metalloproteinase 9 therapeutic use, Protein Phosphatase 2C genetics, Protein Phosphatase 2C metabolism, Proteins metabolism, Tumor Suppressor Proteins metabolism, Subarachnoid Hemorrhage drug therapy, Subarachnoid Hemorrhage metabolism
- Abstract
Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased matrix metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of Smad2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein phosphatase PPM1A and restricted the dephosphorylation of Smad2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce Smad2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.
- Published
- 2022
- Full Text
- View/download PDF