Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Am Heart Assoc. 2012 Oct;1(5):e002584. doi: 10.1161/JAHA.112.002584. Epub 2012 Oct 25.
Mineralocorticoid receptor (MR) antagonists have protective effects in the brain during experimental ischemic stroke, and we have previously demonstrated a key role for myeloid MR during stroke pathogenesis. In this study, we explore both model- and sex-specific actions of myeloid MR during ischemic stroke.
The MR antagonist eplerenone significantly reduced the infarct size in male (control, 99.5 mm(3); eplerenone, 74.2 mm(3); n=8 to 12 per group) but not female (control, 84.0 mm(3); eplerenone, 83.7 mm(3); n=6 to 7 per group) mice after transient (90-minute) middle cerebral artery occlusion. In contrast to MR antagonism, genetic ablation of myeloid MR in female mice significantly reduced infarct size (myeloid MR knockout, 9.4 mm(3) [5.4 to 36.6]; control, 66.0 mm(3) [50.0 to 81.4]; n=6 per group) after transient middle cerebral artery occlusion. This was accompanied by reductions in inflammatory gene expression and improvement in neurological function. In contrast to ischemia-reperfusion, myeloid MR-knockout mice were not protected from permanent middle cerebral artery occlusion. The infarct size and inflammatory response after permanent occlusion showed no evidence of protection by myeloid MR knockout in photothrombotic and intraluminal filament models of permanent occlusion.
These studies demonstrate that MR antagonism is protective in male but not female mice during transient middle cerebral artery occlusion, whereas genetic ablation of myeloid MR is protective in both male and female mice. They also highlight important mechanistic differences in the role of myeloid cells in different models of stroke and confirm that specific myeloid phenotypes play key roles in stroke protection.
在实验性缺血性中风中，盐皮质激素受体 (MR) 拮抗剂对大脑具有保护作用，我们之前已经证明了髓样 MR 在中风发病机制中的关键作用。在这项研究中，我们探索了髓样 MR 在缺血性中风中的模型和性别特异性作用。
MR 拮抗剂依普利酮显著减少了雄性（对照，99.5mm³；依普利酮，74.2mm³；每组 8 至 12 只）而非雌性（对照，84.0mm³；依普利酮，83.7mm³；每组 6 至 7 只）小鼠短暂（90 分钟）大脑中动脉闭塞后的梗死面积。与 MR 拮抗作用相反，雌性小鼠中髓样 MR 的基因缺失显著减少了梗死面积（髓样 MR 敲除，9.4mm³[5.4 至 36.6]；对照，66.0mm³[50.0 至 81.4]；每组 6 只）短暂性大脑中动脉闭塞后。这伴随着炎症基因表达的减少和神经功能的改善。与缺血再灌注不同，髓样 MR 敲除小鼠在永久性大脑中动脉闭塞中不受保护。永久性闭塞后的梗死面积和炎症反应在光血栓形成和管内丝模型的永久性闭塞中，髓样 MR 敲除没有表现出保护作用的迹象。
这些研究表明，MR 拮抗剂在雄性而非雌性小鼠短暂性大脑中动脉闭塞中具有保护作用，而髓样 MR 的基因缺失在雄性和雌性小鼠中均具有保护作用。它们还强调了髓样细胞在不同中风模型中的作用的重要机制差异，并证实了特定的髓样表型在中风保护中发挥关键作用。
