PUBLICATION

Miconazole protects blood vessels from matrix metalloproteinase 9-dependent rupture and hemorrhage

Authors

Yang, R., Zhang, Y., Huang, D., Luo, X., Zhang, L., Zhu, X., Zhang, X., Liu, Z., Han, J., Xiong, J.W.

ID

ZDB-PUB-170206-16

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

Disease Models, Animal
Stroke/complications
Stroke/drug therapy
Stroke/pathology
Matrix Metalloproteinase 9/metabolism*
Miconazole/pharmacology
Miconazole/therapeutic use*
Rupture
Cerebral Hemorrhage/drug therapy
Cerebral Hemorrhage/enzymology*
Cerebral Hemorrhage/pathology
Cerebral Hemorrhage/prevention & control*
Extracellular Matrix/drug effects
Extracellular Matrix/metabolism
Zebrafish
Mutation/genetics
Blood Vessels/pathology
Blood Vessels/ultrastructure
MAP Kinase Signaling System/drug effects
Drug Evaluation, Preclinical
Urokinase-Type Plasminogen Activator/metabolism
Animals

(all 22)

PubMed

28153846 Full text @ Dis. Model. Mech.

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.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
DsRed	arhgef7b^f40a/f40a; s843Tg; sd2Tg	standard conditions	Long-pec	brain nucleate erythrocyte	IFL	Fig. 1
DsRed	s843Tg; sd2Tg	standard conditions	Long-pec	brain nucleate erythrocyte	IFL	Fig. 1
EGFP	arhgef7b^f40a/f40a; hkz04tTg	standard conditions	Long-pec	brain macrophage	IFL	Fig. 1
EGFP	arhgef7b^f40a/f40a; hkz04tTg	standard conditions	Long-pec	brain neutrophil	IFL	Fig. 1
EGFP	arhgef7b^f40a/f40a; s843Tg	control	Protruding-mouth	basilar artery	IFL	Fig. 2
EGFP	arhgef7b^f40a/f40a; s843Tg	chemical treatment by environment: miconazole	Long-pec	basilar artery	IFL	Fig. 2
EGFP	arhgef7b^f40a/f40a; s843Tg	control	Long-pec	basilar artery	IFL	Fig. 2
EGFP	arhgef7b^f40a/f40a; s843Tg	chemical treatment by environment: miconazole	Protruding-mouth	basilar artery	IFL	Fig. 2
EGFP	arhgef7b^f40a/f40a; s843Tg	control	Protruding-mouth	brain vasculature	IFL	Fig. 2
EGFP	arhgef7b^f40a/f40a; s843Tg	control	Long-pec	brain vasculature	IFL	Fig. 2

1 - 10 of 54

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
arhgef7b^f40a/f40a	control	Prim-5	whole organism Ab3-mmp9 labeling increased amount, abnormal	Fig. 6
arhgef7b^f40a/f40a	control	Prim-5	whole organism ab9-mapk labeling increased amount, abnormal	Fig. 6
arhgef7b^f40a/f40a	control	Long-pec	brain hemorrhagic, abnormal	Fig. 2
arhgef7b^f40a/f40a	control	Long-pec	brain hemorrhagic, abnormal	Fig. 3
arhgef7b^f40a/f40a	control	Long-pec	whole organism mmp9 expression increased amount, abnormal	Fig. 3
arhgef7b^f40a/f40a	control	Long-pec	whole organism Ab3-mmp9 labeling increased amount, abnormal	Fig. 3
arhgef7b^f40a/f40a	control	Long-pec to Protruding-mouth	brain hemorrhagic, abnormal	Fig. 6
arhgef7b^f40a/f40a	control	Pec-fin	brain hemorrhagic, abnormal	Fig. 2
arhgef7b^f40a/f40a	control	Pec-fin	brain vasculature structure, abnormal	Fig. 2
arhgef7b^f40a/f40a	control	Pec-fin	nucleate erythrocyte accumulation brain, abnormal	Fig. 2

1 - 10 of 47

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
f40a		Unknown	arhgef7b
hkz04tTg	Tg(coro1a:EGFP)	Transgenic Insertion
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion
sd2Tg	Tg(gata1a:DsRed)	Transgenic Insertion
y7Tg	Tg(fli1:nEGFP)	Transgenic Insertion

1 - 5 of 5

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
cerebrovascular disease	arhgef7b^f40a/f40a	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
arhgef7b^f40a/f40a
arhgef7b^f40a/f40a
arhgef7b^f40a/f40a; hkz04tTg
arhgef7b^f40a/f40a; s843Tg
arhgef7b^f40a/f40a; s843Tg; sd2Tg
arhgef7b^f40a/+; s843Tg
hkz04tTg
s843Tg
s843Tg; sd2Tg
WT

Antibodies

Orthology

Gene	Orthology
mmp9

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP

Mapping

Yang et al., 2017 ZDB-PUB-170206-16 PMID:28153846

Miconazole protects blood vessels from matrix metalloproteinase 9-dependent rupture and hemorrhage

Yang et al., 2017

ZDB-PUB-170206-16
PMID:28153846