Sexual dimorphism in reduced-size liver ischemia and reperfusion injury in mice: Role of endothelial cell nitric oxide synthase
Sexual dimorphism in reduced-size liver ischemia and reperfusion injury in mice: Role of endothelial cell nitric oxide synthase
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DOI：
10.1073/pnas.0235680100
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发表时间：
2003-01-21
影响因子：
11.1
通讯作者：
Grisham, MB
中科院分区：
文献类型：
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作者：
Harada, H;Pavlick, KP;Grisham, MB
我们最近报道了一种雌激素依赖机制，雌性小鼠比雄性小鼠在更大程度上免受小尺寸肝脏缺血再灌注（RSL+I/R）的伤害。本研究的目的是研究在雌性小鼠中观察到的保护作用是否取决于内皮细胞NO合成酶（eNOS）的上调和/或激活。将雌性和雄性野生型或enos缺陷C57BL/6小鼠麻醉后，给予70%肝脏缺血45分钟，然后切除剩余30%非缺血叶，再灌注缺血组织。每天监测生存，而肝损伤则通过血清丙氨酸转氨酶测定和组织病理学来量化。测定RSL+I/R对雄性和雌性小鼠肝脏eNOS mRNA、蛋白和酶活性的影响。我们发现，与雄性小鼠相比，雌性小鼠的肝损伤减轻，存活率提高。与接受手术的男性相比，这种保护作用与肝脏eNOS信息水平和酶活性的显著增加有关，但与蛋白质表达无关。此外，n -omega-硝基- l -精氨酸甲酯治疗或enos缺陷的雌性小鼠对RSL+I/R有反应，肝损伤显著增加，手术2天内死亡率为100%。最后，我们发现普伐他汀预处理显著减轻了雄性小鼠的肝细胞损伤，提高了存活率，这与eNOS信息的表达增强有关。我们得出结论，雌性小鼠的保护作用是由于肝脏eNOS活性的激活和NO生成的增强。
We have recently reported that female mice are protected to a much greater extent from the injurious effects of reduced-size liver ischemia and reperfusion (RSL+I/R) than are males by an estrogen-dependent mechanism. The objective of this study was to examine the possibility that the protective effect observed in female mice depends on the up-regulation and/or activation of endothelial cell NO synthase (eNOS). Anesthetized female and male wild-type or eNOS-deficient C57BL/6 mice were subjected to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of ischemic tissue. Survival was monitored daily, whereas liver injury was quantified by using serum alanine aminotransferase determinations and histopathology. Hepatic eNOS mRNA, protein, and enzymatic activity were determined in male and female mice subjected to RSL+I/R. We found that liver injury was reduced and survival increased in female mice compared with males. This protective effect correlated with significant increases in hepatic eNOS message levels and enzyme activity but not protein expression compared with males subjected to the surgery. Furthermore, N-omega-nitro-L-arginine methyl estertreated or eNOS-deficient female mice responded to RSL+I/R with dramatic increases in liver injury and 100% mortality within 2 days of surgery. Finally, we found that pravastatin pretreatment significantly attenuated hepatocellular injury and increased survival of male mice, which was associated with enhanced expression of eNOS message. We conclude that the protective effect afforded female mice is due to the activation of hepatic eNOS activity and enhanced NO production.