HO1 and Wnt expression is independently regulated in female mice brains following permanent ischemic brain injury

A gender difference in stroke is observed throughout epidemiologic studies, pathophysiology, treatment and outcomes. We investigated the neuroprotective role of hemeoxygenase (HO) enzyme, which catabolizes free heme to bilirubin, carbon monoxide and biliverdin in the female brain after permanent ischemia. We have previously reported in male mice that genetic deletion of HO1 exacerbates the brain damage after permanent ischemia, and the mechanism of neuroprotection is dependent on the HO1/Wnt pathway; however, the role of HO1/Wnt mediated neuroprotection in the female brain is yet to be investigated. We subjected ovary intact female mice, HO1^-/- intact, HO1 inhibitor tin mesoporphyrin (SnMP) treated intact and/or ovariectomized female mice to permanent ischemia (pMCAO), and the animals were sacrificed after 7days. The SnMP treatment for 7days significantly reduced the HO1 enzyme activity as compared to that of vehicle treated group. Infarct volume analysis showed significantly lower infarct in intact, HO1^-/- intact, and SnMP treated group as compared to the OVX group, suggesting the role of estrogen in neuroprotection. However, there were no differences in infarct volume observed between the intact, HO1^-/- and SnMP treated group, suggesting a sexually dimorphic role of HO1 neuroprotection. Western blot analysis on intact and SnMP-treated groups subjected to pMCAO suggested no significant differences in Wnt expression. Together, these results suggest that HO1 neuroprotection is sexually dimorphic and Wnt expression is independently regulated in the female brain following permanent ischemia.