Ischemic Injury-Induced CaMKII? and CaMKII? Confer Neuroprotection Through the NF-?B Signaling Pathway.

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/CaMKII? and CAMK2G/CaMKII? were selectively upregulated in a time-dependent manner at both transcriptional and protein levels after acute ischemia. Overexpression of CaMKII? promoted neuronal survival, while their depletion exacerbated ischemic neuronal death. Similar to CaMKII?, knockdown of CAMKII? resulted in significant neuronal death after I/R. We further identified CaMKII?₂ as the subtype that is selectively induced by I/R in primary neurons. The induction of CaMKII? 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 CaMKII? expression. Knockdown of C2dat1/2 blocked OGD/R-induced CaMKII? expression and decreased neuronal survival but did not affect the levels of CaMKII?, indicating specific targeting of CAMK2D by C2dat1/2. Mechanistically, I/R-induced CaMKII? and CaMKII? caused the upregulation of IKK?/? and further activation of the NF-?B signaling pathway to protect neurons from ischemic damage. Genetically, downregulating p65 subunit of NF-?B in mice increased I/R-induced neuronal death by blocking the activity of CaMKII/IKK/I?B?/NF-?B signaling axis. In summary, CaMKII? and CaMKII? 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-?B signaling pathway, which protects neurons from ischemic damage.

SUBMITTER: Ye J 

PROVIDER: S-EPMC6394630 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature