SHPS-1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative stress.
Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), also known as Signal-regulatory protein alpha (SIRPα) or SIRPA is a transmembrane protein that is predominantly expressed in neurons, dendritic cells, and macrophages. This study was conducted to investigate the role of SHPS-1 in the oxidative stress and brain damage induced by acute focal cerebral ischemia. Wild-type (WT) and SHPS-1 mutant (MT) mice were subjected to middle cerebral artery occlusion (60 min) followed by reperfusion. SHPS-1 MT mice had significantly reduced infarct volumes and improved neurological function after brain ischemia. In addition, neural injury and oxidative stress were inhibited in SHPS-1 MT mice. The mRNA and protein levels of the antioxidant genes nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase 1 were up-regulated in SHPS-1 MT mice. The SHPS-1 mutation suppressed the phosphorylation of SHP-1 and SHP-2 and increased the phosphorylation of Akt and GSK3β. These results provide the first demonstration that SHPS-1 plays an important role in the oxidative stress and brain injury induced by acute cerebral ischemia. The activation of Akt signaling and the up-regulation of Nrf2 and heme oxygenase 1 likely account for the protective effects that were observed in the SHPS-1 MT mice.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China.
Lang
L
Wang
Yanyun
Y
Lu
Shan
S
Deng
Yan
Y
Zhang
Li
L
Yang
Yu
Y
Guan
Takashi
T
Matozaki
Hiroshi
H
Ohnishi
Hong
H
Jiang
Hongliang
H
Li
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology; D002244:Carbon; D004396:Coloring Agents; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D009422:Nervous System Diseases / Q000503:physiopathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics* / Q000502:physiology*; D020521:Stroke / Q000235:genetics* / Q000473:pathology*
D004396:Coloring Agents; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; C028433:chinese ink; D002244:Carbon; D051547:Heme Oxygenase-1; D051058:Oncogene Protein v-akt