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

Abstract

Estrogen (E 2 ) exerts its effect on target organs principally by interacting with specific estrogen receptors (ER) such as ER-␣ or ER-␤. The role that these E 2 receptors play in mediating the protective effects observed in RSLϩI/R induced injury remains to be defined. To study the role of ER-␣, we anesthetized female and male wild type (wt; C57Bl/6) and ER-␣-deficient (␣ERKO) 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 ␣ERKO male mice were injected with E 2 . 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 E 2 survived RSLϩI/R surgery indefinitely whereas all male mice given vehicle died within 3-5 days following surgery. This protective effect was diminished in ␣ERKO female mice such that only 40% of ␣ERKO females survived 7 d following RSLϩI/R. Furthermore, liver injury was significantly higher in ␣ERKO females compared with their wt counterparts and similar to those seen in wild type males and ␣ERKO males. The protective effect observed in wild type females or E 2 treated males correlated well with increases in hepatic eNOS message whereas both male and female ␣ERKO mice exhibited significantly lower levels of eNOS mRNA. We conclude that this protection may in part be due to the E 2 /ER-␣-mediated activation of eNOS. Abbreviations NO, nitric oxide ROS, reactive oxygen species eNOS, endothelial nitric oxide synthase ␣ERKO, estrogen receptor alpha knockout I/R, ischemia/reperfusion wt, wild type RSL؉I/R, reduced-size liver with ischemia and reperfusion injury Hepatic resection with concomitant periods of ischemia and reperfusion (I/R) is a common occurrence in certain surgical procedures such as split liver or living donor transplantation (1, 2). These types of transplantations represent surgical alternatives to whole liver transplantation and are being applied to expand the depleted donor organ pool (1, 2) as well as provide children with size-matched livers. Indeed, the high death rate (7% to 15%) in pediatric liver patients waiting for sizematched cadaveric liver donors (3) has led to the utilization of these types of innovative surgical techniques such as living related transplants (LRT), the reduced size (cut-down) liver grafts and split grafts. These technical advances have led to the reduction in the waiting list mortality (4), however, the success has been fraught with difficulties, medical as well as ethical. For example, the hepatocellular injury induced by I/R is known to impair liver regeneration and may lead to primary graft dysfunction and failure (2, 5, 6). The mechanisms by which RSLϩI/R promotes liver injury are not clear at the present time. However, numerous experimental studies using warm, full-size liver I/R indicate...

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