DNA2,a multifunctional enzyme with structure-specific nuclease,5'-to-3'helicase,and DNA-dependent ATPase activities,plays a pivotal role in the cellular response to DNA damage.However,its involvement in cerebr...DNA2,a multifunctional enzyme with structure-specific nuclease,5'-to-3'helicase,and DNA-dependent ATPase activities,plays a pivotal role in the cellular response to DNA damage.However,its involvement in cerebral ischemia/reperfusion(I/R)injury remains to be elucidated.This study investigated the involvement of DNA2 in cerebral I/R injury using conditional knockout(cKO)mice(Nestin-Cre)subjected to middle cerebral artery occlusion(MCAO),an established model of cerebral I/R.Results demonstrated a gradual up-regulation of DNA2 expression,peaking at 72 h post-MCAO.Notably,DNA2 cKO mice exhibited more pronounced brain injury,neurological deficits,and neuronal apoptosis within the penumbra following MCAO.Additionally,DNA2 expression was elevated in an oxygen-glucose deprivation/reoxygenation(OGD/R)cell culture model,and DNA2 knockdown(KD)exacerbated neuronal apoptosis and oxidative stress.Transcriptome analysis of ischemic penumbra tissues via RNA sequencing revealed significant down-regulation of Homer1 in DNA2 cKO mice.Furthermore,in vitro experiments demonstrated that overexpression of Homer1a ameliorated DNA2 KD-induced neuronal apoptosis.Collectively,these findings demonstrate that DNA2 deficiency exacerbates cerebral I/R injury through the down-regulation of Homer1a,highlighting a novel regulatory axis in ischemic neuroprotection.展开更多
基金supported by the National Natural Science Foundation of China (32070979)Shenzhen Science and Technology Program (JCYJ20220530161604009,JCYJ20240813150734043)+3 种基金Key Research and Development Program of Shaanxi (2024SF,YBXM,050)Fundamental Research Funds for the Central Universities (31020190QD004,3102019YX01001)Double First-Class Project of China Pharmaceutical University (CPUQNJC22_02)Global Pharmaceutical Development Alliance Plan of China Pharmaceutical University (1302090024-05)。
文摘DNA2,a multifunctional enzyme with structure-specific nuclease,5'-to-3'helicase,and DNA-dependent ATPase activities,plays a pivotal role in the cellular response to DNA damage.However,its involvement in cerebral ischemia/reperfusion(I/R)injury remains to be elucidated.This study investigated the involvement of DNA2 in cerebral I/R injury using conditional knockout(cKO)mice(Nestin-Cre)subjected to middle cerebral artery occlusion(MCAO),an established model of cerebral I/R.Results demonstrated a gradual up-regulation of DNA2 expression,peaking at 72 h post-MCAO.Notably,DNA2 cKO mice exhibited more pronounced brain injury,neurological deficits,and neuronal apoptosis within the penumbra following MCAO.Additionally,DNA2 expression was elevated in an oxygen-glucose deprivation/reoxygenation(OGD/R)cell culture model,and DNA2 knockdown(KD)exacerbated neuronal apoptosis and oxidative stress.Transcriptome analysis of ischemic penumbra tissues via RNA sequencing revealed significant down-regulation of Homer1 in DNA2 cKO mice.Furthermore,in vitro experiments demonstrated that overexpression of Homer1a ameliorated DNA2 KD-induced neuronal apoptosis.Collectively,these findings demonstrate that DNA2 deficiency exacerbates cerebral I/R injury through the down-regulation of Homer1a,highlighting a novel regulatory axis in ischemic neuroprotection.
