ZFIN ID: ZDB-PUB-170206-16
Miconazole protects blood vessels from matrix metalloproteinase 9-dependent rupture and hemorrhage
Yang, R., Zhang, Y., Huang, D., Luo, X., Zhang, L., Zhu, X., Zhang, X., Liu, Z., Han, J., Xiong, J.W.
Date: 2017
Source: Disease models & mechanisms   10(3): 337-348 (Journal)
Registered Authors: Xiong, Jing-Wei, Zhang, Xiaolin
Keywords: chemical screen, hemorrhage, miconazole, mmp9, stroke, zebrafish
MeSH Terms:
  • Animals
  • Blood Vessels/pathology
  • Blood Vessels/ultrastructure
  • Cerebral Hemorrhage/drug therapy
  • Cerebral Hemorrhage/enzymology*
  • Cerebral Hemorrhage/pathology
  • Cerebral Hemorrhage/prevention & control*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Extracellular Matrix/drug effects
  • Extracellular Matrix/metabolism
  • MAP Kinase Signaling System/drug effects
  • Matrix Metalloproteinase 9/metabolism*
  • Miconazole/pharmacology
  • Miconazole/therapeutic use*
  • Mutation/genetics
  • Rupture
  • Stroke/complications
  • Stroke/drug therapy
  • Stroke/pathology
  • Urokinase-Type Plasminogen Activator/metabolism
  • Zebrafish
PubMed: 28153846 Full text @ Dis. Model. Mech.
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ABSTRACT
Hemorrhagic stroke accounts for 10-15% of all strokes and is strongly associated with mortality and morbidity worldwide, but its prevention and therapeutic interventions remain a major challenge. Here, we report the identification of miconazole as a hemorrhagic suppressor by a small-molecule screen in zebrafish. We found that a hypomorphic mutant fn40a, one of several known β-pix mutant alleles in zebrafish, had the major symptoms of brain hemorrhage, vessel rupture and inflammation as those in hemorrhagic stroke patients. A small-molecule screen with mutant embryos identified the anti-fungal drug miconazole as a potent hemorrhagic suppressor. Miconazole inhibited both brain hemorrhages in zebrafish and mesenteric hemorrhages in rats by decreasing matrix metalloproteinase 9 (MMP9)-dependent vessel rupture. Mechanistically, miconazole downregulated the levels of pErk and Mmp9 to protect vascular integrity in fn40a mutants. Therefore, our findings demonstrate that miconazole protects blood vessels from hemorrhages by downregulating the pERK-MMP9 axis from zebrafish to mammals and shed light on the potential of phenotype-based screens in zebrafish for the discovery of new drug candidates and chemical probes for hemorrhagic stroke.
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