Miconazole protects blood vessels from MMP9-dependent rupture and hemorrhage.
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 mutantfn40a, one of several knownβ-pixmutant 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 infn40amutants. 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.
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China.|State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China.
Ran
R
Yang
Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Yunpei
Y
Zhang
Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Dandan
D
Huang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China.
Xiao
X
Luo
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China.
Liangren
L
Zhang
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China.|State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China.
Xiaojun
X
Zhu
AstraZeneca Asia and Emerging Market Innovative Medicine and Early Development, Shanghai 201203, China.
Xiaolin
X
Zhang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China jingwei_xiong@pku.edu.cn hanjingyan@bjmu.edu.cn zmliu@bjmu.edu.cn.
Zhenming
Z
Liu
Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China jingwei_xiong@pku.edu.cn hanjingyan@bjmu.edu.cn zmliu@bjmu.edu.cn.
Jing-Yan
JY
Han
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China jingwei_xiong@pku.edu.cn hanjingyan@bjmu.edu.cn zmliu@bjmu.edu.cn.|State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China.
Jing-Wei
0000-0001-8438-4782
JW
Xiong
D000818:Animals; D001808:Blood Vessels / Q000473:pathology / Q000648:ultrastructure; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008825:Miconazole / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation / Q000235:genetics; D012421:Rupture; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D015027:Zebrafish
D008825:Miconazole; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9
Chemical screen; Hemorrhage; Miconazole; Mmp9; Stroke; Zebrafish