Miconazole protects blood vessels from MMP9-dependent rupture and hemorrhage

Disease Models & Mechanisms

Xiaolin Zhang¹  Jing-Wei Xiong²  Xiaojun Zhu²  Ran Yang²  Yunpei Zhang³  Jing-Yan Han³  Dandan Huang³  Xiao Luo⁴  Liangren Zhang⁴  Zhenming Liu⁴ 

[1] AstraZeneca Asia and Emerging Market Innovative Medicine and Early Development, Shanghai 201203, China;Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China;Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China;State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China;

关键词: Chemical screen;    Hemorrhage;    Miconazole;    Mmp9;    Stroke;    Zebrafish;   

DOI  :  10.1242/dmm.027268

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown