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Published on: December 9, 2013
Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex
Ryan A Frieler1, Jessica J Ray, He Meng
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Background:
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.
Methods And Results:
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.
Conclusions:
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.
Insights
Mineralocorticoid receptor (MR) antagonism protected male, but not female, mice in transient stroke models. Genetic deletion of myeloid MR protected both sexes, revealing sex- and model-specific roles in stroke pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Cardiovascular Research
Background:
- Mineralocorticoid receptor (MR) antagonists show neuroprotective effects in experimental ischemic stroke.
- Myeloid MR plays a critical role in stroke pathogenesis.
- This study investigates the model- and sex-specific roles of myeloid MR in ischemic stroke.
Purpose of the Study:
- To determine the sex-specific effects of MR antagonism on ischemic stroke outcomes.
- To investigate the role of myeloid MR in different stroke models and sexes.
- To elucidate mechanistic differences in myeloid cell involvement in stroke.
Main Methods:
- Transient and permanent middle cerebral artery occlusion (MCAO) models in mice.
- Administration of MR antagonist eplerenone.
- Genetic ablation of myeloid MR (myeloid MR knockout).
- Assessment of infarct size, inflammatory gene expression, and neurological function.
Main Results:
- Eplerenone reduced infarct size in male but not female mice after transient MCAO.
- Genetic ablation of myeloid MR reduced infarct size and inflammation in both male and female mice after transient MCAO.
- Myeloid MR knockout did not protect against permanent MCAO in any model, indicating transient ischemia-reperfusion specific effects.
Conclusions:
- MR antagonism is protective in male but not female mice during transient MCAO.
- Genetic ablation of myeloid MR is protective in both male and female mice during transient MCAO.
- Myeloid cell roles in stroke are mechanistically diverse and depend on sex and stroke model.
