Open AccessMyeloid Mineralocorticoid Receptor During Experimental Ischemic Stroke: Effects of Model and Sex
Author(s) -
Frieler Ryan A.,
Ray Jessica J.,
Meng He,
Ramnarayanan Sai P.,
Usher Michael G.,
Su Enming J.,
Berger Stefan,
Pinsky David J.,
Lawrence Daniel A.,
Wang Michael M.,
Mortensen Richard M.
Publication year - 2012
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.112.002584
Subject(s) - medicine , eplerenone , mineralocorticoid receptor , cardiology , stroke (engine) , ischemia , middle cerebral artery , pathology , endocrinology , anesthesia , aldosterone , mechanical engineering , engineering
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.