Targeting GPER1 to suppress autophagy as a male-specific therapeutic strategy for iron-induced striatal injury.

ABSTRACT: The functional outcome of intracerebral hemorrhage (ICH) in young male patients are poor than in premenopausal women. After ICH, ferrous iron accumulation causes a higher level of oxidative injury associated with autophagic cell death in striatum of male mice than in females. In rodent model of ferrous citrate (FC)-infusion that simulates iron accumulation after ICH, female endogenous estradiol (E₂) suppresses autophagy via estrogen receptor ? (ER?) and contributes to less injury severity. Moreover, E₂ implantation diminished the FC-induced autophagic cell death and injury in males, whose ER? in the striatum is less than females. Since, no sex difference of ER? was observed in striatum, we delineated whether ER? and G-protein-coupled estrogen receptor 1 (GPER1) mediate the suppressions of FC-induced autophagy and oxidative injury by E₂ in a sex-dimorphic manner. The results showed that the ratio of constitutive GPER1 to ER? in striatum is higher in males than in females. The GPER1 and ER? predominantly mediated suppressive effects of E₂ on FC-induced autophagy in males and antioxidant effect of E₂ in females, respectively. This finding opens the prospect of a male-specific therapeutic strategy targeting GPER1 for autophagy suppression in patients suffering from iron overload after hemorrhage.

SUBMITTER: Chen TY 

PROVIDER: S-EPMC6491488 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature