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

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 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 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 down-regulated the levels of pErk and Mmp9 to protect vascular integrity in fn40a mutants. Therefore, our findings have demonstrated that miconazole protects blood vessels from hemorrhages by down-regulating the pERK-MMP9 axis from zebrafish to mammals and have shed light on the potential of phenotype-based screens in zebrafish for the discovery of new drug candidates and chemical probes for hemorrhagic stroke.