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Sex-based eRNA expression and function in ischemic stroke.

ABSTRACT: Enhancer-derived RNAs (eRNAs) are a new class of long noncoding RNA that have roles in modulating enhancer-mediated gene transcription, which ultimately influences phenotypic outcomes. We recently published the first study mapping genome-wide eRNA expression in the male mouse cortex during ischemic stroke and identified 77 eRNAs that were significantly altered following a 1 h middle cerebral artery occlusion (MCAO) and 6 h of reperfusion, as compared to sham controls. Knockdown of one such stroke-induced eRNA - eRNA_06347 - resulted in significantly larger infarcts, demonstrating a role for eRNA_06347 in modulating the post-stroke pathophysiology in males. In the current study, we applied quantitative real-time PCR to evaluate whether the 77 eRNAs identified in the male cortex also show altered expression in the post-stroke female cortex. Using age-matched and time-matched female mice, we found that only a subset of the 77 eRNAs were detected in the post-stroke female cortex. Of these, only a small fraction showed similar temporal expression characteristics as males, including eRNA_06347 which was highly induced in both sexes. Knockdown of eRNA_06347 in the female cortex resulted in significantly increased infarct volumes that were closely matched to those in males, indicating that eRNA_06347 modulates the post-stroke pathophysiology similarly in males and females. This suggests a common underlying role for eRNA_06347 in the two sexes. Overall, this is the first study to evaluate eRNA expression and perturbation in the female cortex during stroke, and present a comparative analysis between males and females. Our findings show that eRNAs have sex-dependent and sex-independent expression patterns that may be of significance to the pathophysiological responses to stroke in the two sexes.

SUBMITTER: Ruiz D

PROVIDER: S-EPMC8511075 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Sex-based eRNA expression and function in ischemic stroke.

Ruiz Diandra D Bhattarai Sunil S Dharap Ashutosh A

Neurochemistry international 20210803

Enhancer-derived RNAs (eRNAs) are a new class of long noncoding RNA that have roles in modulating enhancer-mediated gene transcription, which ultimately influences phenotypic outcomes. We recently published the first study mapping genome-wide eRNA expression in the male mouse cortex during ischemic stroke and identified 77 eRNAs that were significantly altered following a 1 h middle cerebral artery occlusion (MCAO) and 6 h of reperfusion, as compared to sham controls. Knockdown of one such strok ...[more]

PMID: 34358636

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Project description:BackgroundSex differences in stroke outcomes have been noted, but whether this extends to stroke recurrence is unclear. We examined sex differences in recurrent stroke using data from the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial.Patients and methodsWe assessed the risk of recurrent stroke in women compared to men using data from the POINT trial. Adults >18 years old were randomized within 12 hours of onset of minor ischemic stroke or transient ischemic attack (TIA), and followed for up to 90 days for ischemic stroke, our primary outcome. We used Cox proportional hazards model adjusted for demographics and stroke risk factors to evaluate the association between sex and stroke recurrence. We used interaction term testing and prespecified subgroup analyses to determine if the association between sex and recurrent stroke differed by age (<60 versus >60 years old), locale (US versus non-US), and index event type (stroke versus TIA). Last, we evaluated whether sex modified the effect of common stroke risk factors on stroke recurrence.ResultsOf 4,881 POINT trial participants with minor stroke or high-risk TIA, 2,195 (45%) were women. During the 90-day follow-up period, 267 ischemic strokes occurred; 121 were in women and 146 in men. The cumulative risk of recurrent ischemic stroke was not significantly different among women (5.76%; 95% CI, 4.84%-6.85%) compared to men (5.67%; 95% CI, 4.83%-6.63%). Women were not at a different risk of recurrent ischemic stroke compared to men (hazard ratio [HR], 1.02; 95% CI, 0.80-1.30) in unadjusted models or after adjusting for covariates. However, there was a significant interaction of age with sex (P=0.04). Among patients <60 years old, there was a non-significantly lower risk of recurrent stroke in women compared to men (HR 0.66; 95% CI 0.42-1.05). Last, sex did not modify the association between common stroke risk factors and recurrent stroke risk.Discussion and conclusionAmong patients with minor stroke or TIA, the risk of recurrent ischemic stroke and the impact of common stroke risk factors did not differ between men and women.

Project description:Background and Purpose- We determined the effect of sex on outcome after endovascular stroke thrombectomy in acute ischemic stroke, including lifelong disability outcomes. Methods- We analyzed patients treated with the Solitaire stent retriever in the combined SWIFT (Solitaire FR With the Intention for Thrombectomy), STAR (Solitaire FR Thrombectomy for Acute Revascularization), and SWIFT PRIME (Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment) cohorts. Ordinal and logistic regression were used to examine known factors influencing outcome after endovascular stroke thrombectomy and study the effect of sex on the association between these factors and outcomes, including age and time to reperfusion. Years of optimal life after thrombectomy were defined as disability-adjusted life years and calculated by projecting disability through adjusted poststroke life expectancy by sex. Results- Among 389 patients treated with endovascular stroke thrombectomy, 55% were females, and median National Institutes of Health Stroke Scale was 17 (interquartile range, 8-28). There were no differences between females versus males in presenting deficit severity (National Institutes of Health Stroke Scale score, 17 versus 17, P=0.21), occlusion location (69% versus 64% M1, P=0.62), presenting infarct extent (Alberta Stroke Program Early CT Score 8 versus 8, P=0.24), rate of substantial reperfusion (Thrombolysis in Cerebral Infarction 2b/3, 87% versus 83%, P=0.37), onset to reperfusion time (294 versus 302 minutes, P=0.46). Despite older ages (69 versus 64, P<0.001) and higher rate of atrial fibrillation (45% versus 30%, P=0.002) for females compared with males, adjusted rates of functional independence at 90 days were similar (odds ratio, 1.0; 95% CI, 0.6-1.6). After adjusting for age at presentation and stroke severity, females had more years of optimal life (disability-adjusted life year) after endovascular stroke thrombectomy, 10.6 versus 8.5 years (P<0.001). Conclusions- Despite greater age and higher rate of atrial fibrillation, females experienced comparable functional outcomes and greater years of optimal life after intervention compared with males.

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Sex-based eRNA expression and function in ischemic stroke.

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Sex-based eRNA expression and function in ischemic stroke.

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