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.
Highlights
Introduction published maps and institutional affilEpidemiologic and clinical evidence have demonstrated the importance of sex differences in the incidence and response to ischemic brain injury [1,2,3]
Focal transient cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion as described previously [29,30]
To determine if differences exist in the pathophysiology of ischemic injury by inhibiting autophagy between male and female mice, we measured the infarct volume 72 h after
Summary
Epidemiologic and clinical evidence have demonstrated the importance of sex differences in the incidence and response to ischemic brain injury [1,2,3]. Women have lower stroke incidence relative to men until well after menopause; rates climb dramatically in elderly women who have greater disability, morbidity and mortality after stroke than men [2,4]. Previous studies have suggested that sex-dependent pathways are activated in response to stroke, including caspase-dependent apoptosis and poly (ADPribose) polymerase-mediated DNA repair [5,6,7,8]. With the cost of stroke care in the USA projected to exceed 180 billion dollars by 2030, understanding sex differences and optimizing neuroprotective agents is critical to the development of efficacious therapies [9,10,11]. Macroautophagy (called autophagy thereafter) is a self-catabolic process where subcellular proteins, macromolecules, and organelles are sequestered within membrane-enclosed vesicles (autophagosomes) and are degraded by fusion with lysosomes (autolysosomes) [12,13,14,15]. iations.
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