Sestrin2 Attenuates Cerebral Injury By Activating Nrf2 Following Photothrombotic Stroke In Rats

Background and Purpose: The lack of effective treatments for ischemic stroke is concerning.Here,we aimed to examine the protective effects of sestrin2 in ischemic stroke and determine the mechanism by which sestrin2 attenuates cerebral injuries.Methods: Ischemic stroke was induced in Sprague-Dawley rats using a photothrombotic ischemia(PTI)model.After sestrin2 was overexpressed or silenced,neurological deficits and brain infarction were evaluated.Cerebral angiogenesis and the expression of related proteins were examined by Western blotting and immunofluorescence.The interaction between p62 and Keap1 was measured by coimmunoprecipitation(CoIP)and an in situ proximity ligation assay(PLA).Results: The overexpression of sestrin2 was found to improve the neurological function of rats 10 days after PTI and to reduce the infarct volume in rats 10 days after PTI.It was shown that upregulating sestrin2 enhanced the relative immunofluorescence intensity of CD31,CD34 and DCX and increased the expression of nuclear and total Nrf2,HO-1,VEGF and p62.However,downregulating sestrin2 induced almost the opposite results.Furthermore,we demonstrated that sestrin2 increased the interaction between p62 and Keap1.Conclusion: Based on our data,sestrin2 may promote angiogenesis by activating the Nrf2 pathway through increasing the interaction between p62 and Keap1 via upregulating p62 expression.