Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke
Anthony N. Patrizz,
Jose F. Moruno-Manchon,
Lena M. O’Keefe,
Sarah J. Doran,
Anita R. Patel,
Venugopal R. Venna,
Andrey S. Tsvetkov,
Jun Li,
Louise D. McCullough
Affiliations
Anthony N. Patrizz
Department of Neurology, McGovern Medical School at the University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Jose F. Moruno-Manchon
Department of Neurology, McGovern Medical School at the University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Lena M. O’Keefe
Department of Neurology, Beth Israel Deaconess Hospital, 330 Brookline Avenue, Boston, MA 02215, USA
Sarah J. Doran
Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
Anita R. Patel
Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
Venugopal R. Venna
Department of Neurology, McGovern Medical School at the University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Andrey S. Tsvetkov
Department of Neurology, McGovern Medical School at the University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Jun Li
Department of Neurology, McGovern Medical School at the University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
Louise D. McCullough
Department of Neurology, McGovern Medical School at the University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA
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.
