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  • Accumulated evidence indicates that apelin plays a protectiv


    Accumulated evidence indicates that apelin plays a protective role in ischemic stroke, contributing to post-stroke recovery (Yang et al., 2014; Chen et al., 2015; Xin et al., 2015; Yan et al., 2015). Apelin gene (APLN) encodes prepro-apelin with 77 amino acids, while the C-terminal 23 they have to say are 100% conserved among human, rat, mouse and bovine. Prepro-apelin can be cleaved into various peptides with 13, 17, and 36 amino acids from the C-terminus, while apelin-13 shows the strongest biological activity (Wu et al., 2017). Apelin-13 is an endogenous ligand of apelin receptor (APLNR). As a member of G-protein-coupled receptor (GPCR), APLNR mainly mediates signal transduction via Ga subunit (Gαi or Gαq) of G protein (Wu et al., 2017). Previous studies showed that apelin protects neurons from I/R-induced apoptosis (Yang et al., 2014; Chen et al., 2015; Xin et al., 2015; Yan et al., 2015). Our recent work showed that apelin reduces I/R injury-induced CHOP elevation (Qiu et al., 2017). However, the effect of apelin-13 on ERS-induced eIF2-ATF4-CHOP activation in ischemic stroke remains elusive. Moreover, the effect of apelin-13 on CK2 regulation and CK2 mediated-ERS in ischemic stroke is still unknown. In this study, we showed that the expression of casein kinase 2 (CK2) was significantly reduced by cerebral I/R injury in rats, which was associated with the activation of eIF2-ATF4-CHOP signaling pathway, leading to neuronal apoptosis. Moreover, we found that apelin-13 significantly upregulated CK2 expression and inhibited eIF2-ATF4-CHOP activation, attenuating cerebral I/R injury-induced infarct and neuronal apoptosis in rats. Furthermore, we demonstrated that the rescue effect of apelin-13 on I/R injury-induced neuronal apoptosis was mediated by Gαi/Gαq-CK2-dependent inhibition of eIF2-ATF4-CHOP activation. These data indicated cerebral I/R injury reduced CK2 expression and activated eIF2-ATF4-CHOP signaling contributing to neuronal apoptosis, and apelin-13 can activate Gαi/Gαq-CK2 signaling attenuating eIF2-ATF4-CHOP-mediated neuronal apoptosis. It provides a novel insight that not only apelin-13 but also CK2 agonists may have therapeutic potential for protecting neurons from I/R injury-induced apoptosis, facilitating post-stroke recovery.
    Materials and methods
    Discussion Ischemic stroke is a devastating cerebrovascular disease with high morbidity, leading to death and disability (Mozaffarian et al., 2016). Protecting against penumbra cell apoptosis is a major strategy to improve post-stroke recovery. Accumulated evidence indicates that ERS/UPR plays a major role in I/R injury-induced neuronal apoptosis in ischemic stroke (Wu et al., 2017). PERK-CHOP branch is a major arm of UPR contributing to apoptosis. Although Nakka et al. showed that cerebral I/R injury increased the expression of ATF4 and CHOP at mRNA level, the activation of PERK-CHOP branch has not been precisely investigated in cerebral I/R injury (Nakka et al., 2010). In this study, we found that the downstream molecules of PERK activation, p-eIF2α, ATF4 and CHOP, were upregulated by cerebral I/R injury in a time-dependent manner and the maximum elevation was reached at 24 h post-reperfusion, which contributed to CHOP-mediated apoptosis. The expression of GRP78 was also increased by cerebral I/R injury with a peak point at 12 h post-reperfusion. GRP78 is not only upregulated by PERK activation but also increased by the activation of IRE1 and ASTF6 branches, which might lead the expression of GRP78 to reach the peak point earlier than p-eIF2α, ATF4 and CHOP. Moreover, the activation of p-eIF2α-ATF4-CHOP signaling was persistent until 72 h post-reperfusion, suggesting that there is a relative long time-window for stroke treatment by inhibiting CHOP-mediated apoptosis compared with the narrow time window of thrombolytic therapy which is a widely applied clinical treatment. Consistently, temporal activation of p-eIF2α-ATF4-CHOP signaling and neuronal apoptosis was observed in primary neurons exposed to I/R injury, indicating that I/R injury-induced apoptosis is associated with the activation of p-eIF2α-ATF4-CHOP in neurons. Therefore, inhibiting ERS-mediated p-eIF2α-ATF4-CHOP/GRP78 signaling might be a potential approach to protect I/R injury-induced neuronal apoptosis in ischemic stroke.