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Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke.

ABSTRACT: Ischemic stroke triggers a series of complex pathophysiological processes including autophagy. Differential activation of autophagy occurs in neurons derived from males versus females after stressors such as nutrient deprivation. Whether autophagy displays sexual dimorphism after ischemic stroke is unknown. We used a cerebral ischemia mouse model (middle cerebral artery occlusion, MCAO) to evaluate the effects of inhibiting autophagy in ischemic brain pathology. We observed that inhibiting autophagy reduced infarct volume in males and ovariectomized females. However, autophagy inhibition enhanced infarct size in females and in ovariectomized females supplemented with estrogen compared to control mice. We also observed that males had increased levels of Beclin1 and LC3 and decreased levels of pULK1 and p62 at 24 h, while females had decreased levels of Beclin1 and increased levels of ATG7. Furthermore, the levels of autophagy markers were increased under basal conditions and after oxygen and glucose deprivation in male neurons compared with female neurons in vitro. E2 supplementation significantly inhibited autophagy only in male neurons, and was beneficial for cell survival only in female neurons. This study shows that autophagy in the ischemic brain differs between the sexes, and that autophagy regulators have different effects in a sex-dependent manner in neurons.

SUBMITTER: Patrizz AN

PROVIDER: S-EPMC8304137 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke.

Patrizz Anthony N AN Moruno-Manchon Jose F JF O'Keefe Lena M LM Doran Sarah J SJ Patel Anita R AR Venna Venugopal R VR Tsvetkov Andrey S AS Li Jun J McCullough Louise D LD

Cells 20210720 7

Ischemic stroke triggers a series of complex pathophysiological processes including autophagy. Differential activation of autophagy occurs in neurons derived from males versus females after stressors such as nutrient deprivation. Whether autophagy displays sexual dimorphism after ischemic stroke is unknown. We used a cerebral ischemia mouse model (middle cerebral artery occlusion, MCAO) to evaluate the effects of inhibiting autophagy in ischemic brain pathology. We observed that inhibiting autop ...[more]

PMID: 34359998

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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.

Project description:IntroductionStroke is a disease that presents with well-known sex differences. While women account for more stroke deaths, recent data show that after adjusting for age and pre-stroke functional status, mortality is higher in men. Immune responses are key determinants of stroke outcome and may differ by sex. This study examined sex differences in central and peripheral T cell immune responses, systemic effects on gut permeability and microbiota diversity and behavioral outcomes after stroke in aged mice. We hypothesized that there are sex differences in the immune response to stroke in aged animals.MethodsC57BL/6CR mice (20-22 months) were subjected to 60 min middle cerebral artery occlusion, or sham surgery. T cells were quantified in brain and blood at 3, 7 and 15 days (d) post-stroke by flow cytometry. Peripheral effects on gut permeability and microbiota diversity, as well as neurological function were assessed up to 14 d, and at 21 d (cognitive function) post-stroke. Brain glial fibrillary acidic protein (GFAP) expression was evaluated at 42 d post-stroke.Results and discussionMortality (50% vs 14%, p < 0.05) and hemorrhagic transformation (44% vs 0%) were significantly higher in males than in females. No difference in infarct size at 3d were observed. Peripherally, stroke induced greater gut permeability of FITC-dextran in males at d3 (p < 0.05), and non-reversible alterations in microbiota diversity in males. Following the sub-acute phase, both sexes demonstrated a time-dependent increase of CD4+ and CD8+ T cells in the brain, with significantly higher levels of CD8+ T cells and Regulatory T cells in males at d15 (p < 0.01). Aged males demonstrated greater neurological deficits up to d5 and impaired sensorimotor function up to d15 when assessed by the corner asymmetry test (p < 0.001 and p < 0.01, respectively). A trend in greater cognitive decline was observed at d21 in males. Increased GFAP expression in the ischemic hemisphere, indicating astroglial activation and gliosis, was demonstrated in both males and females 42d post-stroke. Our findings indicate that despite a similar initial ischemic brain injury, aged male mice experience greater peripheral effects on the gut and ongoing central neuroinflammation past the sub-acute phase after stroke.

Project description:ObjectiveHigh-risk intracranial arterial plaques are the most common cause of ischemic stroke and their characteristics vary between male and female patients. However, sex differences in intracranial plaques among symptomatic patients have rarely been discussed. This study aimed to evaluate sex differences in intracranial atherosclerotic plaques among Chinese patients with cerebral ischemia.MethodsOne hundred and ten patients who experienced ischemic events underwent 3T cardiovascular magnetic resonance vessel wall scanning for the evaluation of intracranial atherosclerotic disease. Each plaque was classified according to its likelihood of causing a stroke (as culprit, uncertain, or non-culprit). The outer wall area (OWA) and lumen area of the lesion and reference sites were measured, and the wall and plaque areas, remodeling ratio, and plaque burden (characterized by a normalized wall index) were further calculated. The composition (T1 hyperintensity, enhancement) and morphology (surface irregularity) of each plaque were analyzed. Sex differences in intracranial plaque characteristics were compared between male and female patient groups.ResultsOverall, 311 plaques were detected in 110 patients with ischemic stroke (81 and 29 male and female patients, respectively). The OWA (P < 0.001) and wall area (P < 0.001) of intracranial arterial lesions were significantly larger in male patients. Regarding culprit plaques, the plaque burden in male patients was similar to that in female patients (P = 0.178, odds ratio [OR]: 0.168, 95% confidence interval [CI]: -0.020 to 0.107). However, the prevalence of plaque T1 hyperintensity was significantly higher than that in female patients (P = 0.005, OR: 15.362, 95% CI: 2.280-103.49). In the overall ischemic stroke sample, intracranial T1 hyperintensity was associated with male sex (OR: 13.480, 95% CI: 2.444-74.354, P = 0.003), systolic blood pressure (OR: 1.019, 95% CI: 1.002-1.036, P = 0.031), and current smoker (OR: 3.245, 95% CI: 1.097-9.598, P = 0.033).ConclusionFor patients with ischemic stroke, the intracranial plaque burden in male patients was similar to that in female patients; however, the plaque characteristics in male patients are associated with higher risk, especially in culprit plaques.

Dataset Information

Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke.

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Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke.

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