Ischemic Injury-Induced CaMKII δ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway

AbstractCa2+/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 thatCAMK2D/CaMKII δ andCAMK2G/CaMKII γ 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 signifi cant 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 CaMKII δ was controlled in part by a pair of long non-coding RNAs (lncRNAs),C2dat1 andC2dat2.C2dat2, similar toC2dat1, was upregulated by I/R and cooperated withC2dat1 to modulate CaMKII δ expression. Knockdown ofC2dat1/2 blocked OGD/R-induced CaMKII δ expression and decreased neuronal survival but did not affect the levels of CaMKIIγ, indicating specific targeting ofCAMK2D byC2dat1/2. Mechanistically, I/R-induced CaMKII δ 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 ac...

Source: Molecular Neurobiology - July 11, 2018 Category: Neurology Source Type: research