title: Sestrin2 Silencing Exacerbates Cerebral Ischemia/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK/PGC-1α Pathway in Rats.
abstract: Sestrin2 (Sesn2) exerts neuroprotective properties in some neurodegenerative diseases. However, the role of Sesn2 in stroke is unclear. The AMP-activated protein kinase/peroxisome proliferator-activated receptor γ coactivator-1α (AMPK/PGC-1α) pathway plays an important role in regulating mitochondrial biogenesis, which helps prevent cerebral ischemia/reperfusion (I/R) injury. Here, we aimed to determine whether Sesn2 alleviated I/R damage by regulating mitochondrial biogenesis through the AMPK/PGC-1α signaling pathway. To be able to test this, Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h with Sesn2 silencing. At 24 h after reperfusion, we found that neurological deficits were exacerbated, infarct volume was enlarged, and oxidative stress and neuronal damage were greater in the Sesn2 siRNA group than in the MCAO group. To explore protective mechanisms, an AMPK activator was used. Expression levels of Sesn2, p-AMPK, PGC-1α, NRF-1, TFAM, SOD2, and UCP2 were significantly increased following cerebral I/R. However, upregulation of these proteins was prevented by Sesn2 small interfering RNA (siRNA). In contrast, activation of AMPK with 5'-aminoimidazole-4-carboxamide riboside weakened the effects of Sesn2 siRNA. These results suggest that Sesn2 silencing may suppress mitochondrial biogenesis, reduce mitochondrial biological activity, and finally aggravate cerebral I/R injury through inhibiting the AMPK/PGC-1α pathway.
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.|Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Lina
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.|Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Yanghao
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.|Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.|Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.|Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.|Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.|Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.|Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China.|Institute of Neuroscience, Chongqing Medical University, Chongqing, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D020868:Gene Silencing; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics* / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics; D020521:Stroke / Q000235:genetics* / Q000503:physiopathology; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering; C501429:Ppargc1a protein, rat; C583887:Sesn2 protein, rat; D000084622:Sestrins; C568305:Prkaa1 protein, rat