Abstract
Stroke occurs with greater frequency in men than in women across diverse ethnic backgrounds and nationalities. Work from our lab and others have revealed a sex-specific sensitivity to cerebral ischemia whereby males exhibit a larger extent of brain damage resulting from an ischemic event compared to females. Previous studies revealed that microRNA (miRNA) expression is regulated by cerebral ischemia in males; however, no studies to date have examined the effect of ischemia on miRNA responses in females. Thus, we examined miRNA responses in male and female brain in response to cerebral ischemia using miRNA arrays. These studies revealed that in male and female brains, ischemia leads to both a universal miRNA response as well as a sexually distinct response to challenge. Target prediction analysis of the miRNAs increased in male or female ischemic brain reveal sex-specific differences in gene targets and protein pathways. These data support that the mechanisms underlying sexually dimorphic responses to cerebral ischemia includes distinct changes in miRNAs in male and female brain, in addition to a miRNA signature response to ischemia that is common to both.
Highlights
Stroke occurs more frequently in men than women across diverse ethnic backgrounds and nationalities (Bushnell, 2008; Reeves et al, 2008; Saini and Shuaib, 2008; Appelros et al, 2009; Persky et al, 2010; Ovbiagele et al, 2013; Towfighi et al, 2013)
Our lab and others have shown that sensitivity to cerebral ischemia, i.e., the extent of brain damage resulting from ischemic insult, is sex-specific, with female animals being less sensitive than males (Murphy et al, 2004; Koerner et al, 2007; Lang and McCullough, 2008; Reeves et al, 2008; Vagnerova et al, 2008; Cheng and Hurn, 2010; Siegel et al, 2010)
Sex differences in ischemic sensitivity have been extended to the cellular level as our lab and others have shown that astrocytes (Liu et al, 2007, 2008) and neurons (Li et al, 2005; Johnsen and Murphy, 2011) from male newborn rodents are more sensitive to oxygen-glucose deprivation than cells from female newborn rodents
Summary
Stroke occurs more frequently in men than women across diverse ethnic backgrounds and nationalities (Bushnell, 2008; Reeves et al, 2008; Saini and Shuaib, 2008; Appelros et al, 2009; Persky et al, 2010; Ovbiagele et al, 2013; Towfighi et al, 2013). Sex differences in ischemic sensitivity have been extended to the cellular level as our lab and others have shown that astrocytes (Liu et al, 2007, 2008) and neurons (Li et al, 2005; Johnsen and Murphy, 2011) from male newborn rodents are more sensitive to oxygen-glucose deprivation (an in vitro model of ischemia) than cells from female newborn rodents. These observations suggest that the male brain exhibits a more “ischemia-sensitive” phenotype than the female brain. The underlying molecular mechanisms for this sexually dimorphic response to ischemia are not well understood
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