Estrogen Receptor-α, Sexual Dimorphism and Reduced-Size Liver Ischemia and Reperfusion Injury in Mice

Estrogen (E₂) exerts its effect on target organs principally by interacting with specific estrogen receptors (ER) such as ER-α or ER-β. The role that these E₂ receptors play in mediating the protective effects observed in RSL+I/R induced injury remains to be defined. To study the role of ER-α, we anesthetized female and male wild type (wt; C57B1/6) and ER-α-deficient (αERKO) mice and subjected them to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of the ischemic tissue. For some experiments, wt and αERKO male mice were injected with E₂. Survival was monitored on a daily basis while liver injury was assessed by quantifying serum alanine aminotransferase (ALT) levels and histopathology. Hepatic eNOS mRNA levels were evaluated using semi-quantitative RT-PCR. Our data showed that untreated females or males treated with E₂ survived RSL+I/R surgery indefinitely whereas all male mice given vehicle died within 3-5 days following surgery. This protective effect was diminished in αERKO female mice such that only 40% of αERKO females survived 7 d following RSL+I/R. Furthermore, liver injury was significantly higher in αERKO females compared with their wt counterparts and similar to those seen in wild type males and αERKO males. The protective effect observed in wild type females of E₂ treated males correlated well with increases in hepatic eNOS message whereas both male and female αERKO mice exhibited significantly lower levels of eNOS mRNA. We conclude that this protection may in part be due to the E₂/ER-α-mediated activation of eNOS.