Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage

Sci Adv. 2022 Sep 30;8(39):eabq2423. doi: 10.1126/sciadv.abq2423. Epub 2022 Sep 30.


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.

MeSH terms

  • 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
  • Subarachnoid Hemorrhage* / drug therapy
  • Subarachnoid Hemorrhage* / metabolism
  • Tumor Suppressor Proteins / metabolism


  • NDRG2 protein, human
  • Proteins
  • Tumor Suppressor Proteins
  • PPM1A protein, human
  • Protein Phosphatase 2C
  • Matrix Metalloproteinase 9