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ZIPK mediates endothelial cell contraction through myosin light chain phosphorylation and is required for ischemic‐reperfusion injury
- Source :
- FASEB J
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- The paracellular gap formed by endothelial cell (EC) contraction is fundamental for endothelium permeability, but the mechanism underlying EC contraction has yet to be determined. Here, we identified the zipper-interacting protein kinase (ZIPK) as the kinase for EC contraction and myosin light chain (MLC) phosphorylation. Inhibition of ZIPK activity by pharmacological inhibitors and small interfering RNAs led to a significant decrease in the mono- and diphosphorylation of MLCs along with a contractile response to thrombin, suggesting an essential role of ZIPK in EC paracellular permeability. To assess the role of ZIPK in vivo, we established mouse lines with conditional deletion of Zipk gene. The endothelium-specific deletion of Zipk led to embryonic lethality, whereas the UBC-Cre(ERT2)–mediated deletion of Zipk by tamoxifen induction at adulthood caused no apparent phenotype. The induced deletion of Zipk significantly inhibited ischemia-reperfusion–induced blood-brain barrier dysfunction and neuronal injuries from middle cerebral artery occlusion and reperfusion, as evidenced by reduced infarct and edema volume, attenuated Evans blue dye leakage, and improved neuronal behavior. We thus concluded that ZIPK and its phosphorylation of MLC were required for EC contraction and ischemic neuronal injuries. ZIPK may be a prospective therapeutic target for stroke.—Zhang, Y., Zhang, C., Zhang, H., Zeng, W., Li, S., Chen, C., Song, X., Sun, J., Sun, Z., Cui, C., Cao, X., Zheng, L., Wang, P., Zhao, W., Zhang, Z., Xu, Y., Zhu, M., Chen, H. ZIPK mediates endothelial cell contraction through myosin light chain phosphorylation and is required for ischemic-reperfusion injury.
- Subjects :
- Male
0301 basic medicine
Myosin Light Chains
Myosin light-chain kinase
Contraction (grammar)
Endothelium
Biochemistry
Cell Line
Capillary Permeability
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Pregnancy
Human Umbilical Vein Endothelial Cells
Genetics
medicine
Animals
Humans
RNA, Messenger
Phosphorylation
Protein kinase A
Molecular Biology
Evans Blue
Mice, Knockout
Kinase
Research
Endothelial Cells
Cell biology
Mice, Inbred C57BL
Endothelial stem cell
Death-Associated Protein Kinases
Phenotype
030104 developmental biology
medicine.anatomical_structure
chemistry
Blood-Brain Barrier
Reperfusion Injury
Female
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....d26866e8cc0ac0995956b034cb96cb9e