Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway
Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway
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DOI：
10.1007/s12035-018-1198-2
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Qiming Jane Wang
中科院分区：
文献类型：
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作者：
Jing Ye;Sabyasachi Das;Adhiraj Roy;Wenzhong Wei;Huachen Huang;Joshua Michael Lorenz-Guertin;Qian Xu;Tija C. Jacob;Bing Wang;Dandan Sun;Qiming Jane Wang
Abstract.Ca2+/calmodulin-dependent protein kinase II (CaMKII) has long been implicated in neuronal injury caused by acute ischemia/.reperfusion (I/R). However, its precise role and regulatory mechanisms remain obscure. Here, we investigated the role of the.CaMKII family in neuronal survival during I/R. Our data indicated that CAMK2D/CaMKIIδ and CAMK2G/CaMKIIγ were.selectively upregulated in a time-dependent manner at both transcriptional and protein levels after acute ischemia..Overexpression of CaMKIIδ promoted neuronal survival, while their depletion exacerbated ischemic neuronal death. Similar.to CaMKIIδ, knockdown of CAMKIIγ resulted in significant neuronal death after I/R. We further identified CaMKIIδ2 as the.subtype that is selectively induced by I/R in primary neurons. The induction of CaMKIIδ was controlled in part by a pair of long.non-coding RNAs (lncRNAs), C2dat1 and C2dat2. C2dat2, similar to C2dat1, was upregulated by I/R and cooperated with.C2dat1 to modulate CaMKIIδ expression. Knockdown of C2dat1/2 blocked OGD/R-induced CaMKIIδ expression and decreased neuronal survival but did not affect the levels of CaMKIIγ, indicating specific targeting of CAMK2D by C2dat1/2..Mechanistically, I/R-induced CaMKIIδ and CaMKIIγ caused the upregulation of IKKα/β and further activation of the NF-κB.signaling pathway to protect neurons from ischemic damage. Genetically, downregulating p65 subunit of NF-κB in mice.increased I/R-induced neuronal death by blocking the activity of CaMKII/IKK/IκBα/NF-κB signaling axis. In summary,.CaMKIIδ and CaMKIIγ are novel I/R-induced genes that promote neuronal survival during ischemic injury. The upregulation.of these CaMKII kinases led to activation of the NF-κB signaling pathway, which protects neurons from ischemic damage.
