Protein kinase D2 confers neuroprotection by promoting AKT and CREB activation in ischemic stroke.
Protein kinase D2 confers neuroprotection by promoting AKT and CREB activation in ischemic stroke.
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DOI：
10.1016/j.nbd.2023.106305
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发表时间：
2023-10-15
影响因子：
6.1
通讯作者：
Wang, Q. Jane
中科院分区：
文献类型：
--
作者：
Connelly, Jaclyn A.;Zhang, Xuejing;Chen, Yuzhou;Chao, Yapeng;Shi, Yejie;Jacob, Tija C.;Wang, Q. Jane
缺血性中风占所有中风的80%-90%，是成人死亡和长期残疾的主要原因。迫切需要为这种毁灭性的疾病找到新的靶点和治疗方法。蛋白激酶D(PKD)作为二酰甘油参与脑缺血反应的关键靶点，在缺血性卒中中的作用尚未得到很好的研究，尤其是PKD2。在本研究中，我们发现短暂性局灶性脑缺血后同侧脑内PKD2的表达和活性显著上调，这与体外脑缺血后原代神经元PKD2的表达上调相一致，提示PKD2在缺血性卒中神经元存活中具有潜在的作用。利用PKD2基因敲入(PKD2-KI)小鼠，我们研究了PKD2活性的丧失是否会影响大脑中动脉短暂闭塞(TMCAO)1h和再灌注24h小鼠的卒中结局。我们的数据显示，与野生型(WT)小鼠相比，PKD2-Ki小鼠表现出更大的脑梗塞体积和神经功能评分，表明脑损伤增加，证实了PKD2在缺血/再灌注(I/R)损伤中的神经保护作用。从PKD2-KI小鼠获得的小鼠原代神经元在体外缺血时，与WT神经元相比，细胞死亡也增加。我们进一步确定AKT和CREB是PKD2调节I/R损伤后神经元存活的两个主要信号转导节点。综上所述，PKD2通过促进AKT和CREB的激活而在缺血性卒中发挥神经保护作用，靶向激活PKD2可能有利于缺血性卒中神经元的存活。
Ischemic stroke, constituting 80–90% of all strokes, is a leading cause of death and long-term disability in adults. There is an urgent need to discover new targets and therapies for this devastating condition. Protein kinase D (PKD), as a key target of diacylglycerol involved in ischemic responses, has not been well studied in ischemic stroke, particularly PKD2. In this study, we found that PKD2 expression and activity were significantly upregulated in the ipsilateral side of the brain after transient focal cerebral ischemia, which coincides with the upregulation of PKD2 in primary neurons in response to in vitro ischemia, implying a potential role of PKD2 in neuronal survival in ischemic stroke. Using kinase-dead PKD2 knock-in (PKD2-KI) mice, we examined whether loss of PKD2 activity affected stroke outcomes in mice subjected to 1 h of transient middle cerebral artery occlusion (tMCAO) and 24 h of reperfusion. Our data demonstrated that PKD2-KI mice exhibited larger infarction volumes and worsened neurological scores, indicative of increased brain injury, as compared to the wild-type (WT) mice, confirming a neuroprotective role of PKD2 in ischemia/reperfusion (I/R) injury. Mouse primary neurons obtained from PKD2-KI mice also exhibited increased cell death as compared to the WT neurons when subjected to in vitro ischemia. We have further identified AKT and CREB as two main signaling nodes through which PKD2 regulates neuronal survival during I/R injury. In summary, PKD2 confers neuroprotection in ischemic stroke by promoting AKT and CREB activation and targeted activation of PKD2 may benefit neuronal survival in ischemic stroke.
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DOI：
10.1038/jcbfm.2008.157
发表时间：
2009-04
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
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影响因子：
9
作者：
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Planas, Anna M.
DOI：
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发表时间：
2021-09
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
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作者：
Chandra PK;Cikic S;Baddoo MC;Rutkai I;Guidry JJ;Flemington EK;Katakam PV;Busija DW
通讯作者：
Busija DW
影响因子：
4.8
作者：
Higuero, Alonso M.;Sanchez-Ruiloba, Lucia;Iglesias, Teresa
通讯作者：
Iglesias, Teresa
DOI：
10.1177/0271678x20970048
发表时间：
2021-03
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Sommer CJ;Schäbitz WR
通讯作者：
Schäbitz WR