Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Department of Emergency Medicine, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223001, China.
Oxid Med Cell Longev. 2021 Apr 23;2021:6657529. doi: 10.1155/2021/6657529. eCollection 2021.
The cardioprotective effect of sevoflurane postconditioning (SPostC) is lost in diabetes that is associated with cardiac phosphatase and tensin homologue on chromosome 10 (PTEN) activation and phosphoinositide 3-kinase (PI3K)/Akt inactivation. T-LAK cell-originated protein kinase (TOPK), a mitogen-activated protein kinase- (MAPKK-) like serine/threonine kinase, has been shown to inactivate PTEN (phosphorylated status), which in turn activates the PI3K/Akt signaling (phosphorylated status). However, the functions of TOPK and molecular mechanism underlying SPostC cardioprotection in nondiabetes but not in diabetes remain unknown. We presumed that SPostC exerts cardioprotective effects by activating PTEN/PI3K/Akt through TOPK in nondiabetes and that impairment of TOPK/PTEN/Akt blocks diabetic heart sensitivity to SPostC. We found that in the nondiabetic C57BL/6 mice, SPostC significantly attenuated postischemic infarct size, oxidative stress, and myocardial apoptosis that was accompanied with enhanced p-TOPK, p-PTEN, and p-Akt. These beneficial effects of SPostC were abolished by either TOPK kinase inhibitor HI-TOPK-032 or PI3K/Akt inhibitor LY294002. Similarly, SPostC remarkably attenuated hypoxia/reoxygenation-induced cardiomyocyte damage and oxidative stress accompanied with increased p-TOPK, p-PTEN, and p-Akt in H9c2 cells exposed to normal glucose, which were canceled by either TOPK inhibition or Akt inhibition. However, either in streptozotocin-induced diabetic mice or in H9c2 cells exposed to high glucose, the cardioprotective effect of SPostC was canceled, accompanied by increased oxidative stress, decreased TOPK phosphorylation, and impaired PTEN/PI3K/Akt signaling. In addition, TOPK overexpression restored posthypoxic p-PTEN and p-Akt and decreased cell death and oxidative stress in H9c2 cells exposed to high glucose, which was blocked by PI3K/Akt inhibition. In summary, SPostC prevented myocardial ischemia/reperfusion injury possibly through TOPK-mediated PTEN/PI3K/Akt activation and impaired activation of this signaling pathway may be responsible for the loss of SPostC cardioprotection by SPostC in diabetes.
七氟醚后处理（SPostC）的心脏保护作用在与心脏磷酸酶和张力蛋白同系物 on chromosome 10（PTEN）激活和磷酸肌醇 3-激酶（PI3K）/Akt 失活相关的糖尿病中丧失。T-LAK 细胞源性蛋白激酶（TOPK）是一种丝氨酸/苏氨酸激酶，已被证明可使 PTEN 失活（磷酸化状态），从而激活 PI3K/Akt 信号通路（磷酸化状态）。然而，TOPK 的功能以及 SPostC 在非糖尿病中的心脏保护作用的分子机制尚不清楚，但在糖尿病中则不然。我们推测，SPostC 通过在非糖尿病中激活 TOPK 来发挥对 PTEN/PI3K/Akt 的心脏保护作用，而 TOPK/PTEN/Akt 的损伤会阻止糖尿病心脏对 SPostC 的敏感性。我们发现，在非糖尿病 C57BL/6 小鼠中，SPostC 显著减轻了缺血后梗死面积、氧化应激和心肌凋亡，同时伴有 p-TOPK、p-PTEN 和 p-Akt 的增强。这些 SPostC 的有益作用被 TOPK 激酶抑制剂 HI-TOPK-032 或 PI3K/Akt 抑制剂 LY294002 所消除。同样，SPostC 显著减轻了在正常葡萄糖中暴露的 H9c2 细胞中的缺氧/复氧诱导的心肌损伤和氧化应激，同时伴有 p-TOPK、p-PTEN 和 p-Akt 的增加，而 TOPK 抑制或 Akt 抑制则消除了这些作用。然而，在链脲佐菌素诱导的糖尿病小鼠或在高葡萄糖中暴露的 H9c2 细胞中，SPostC 的心脏保护作用被取消，同时伴有氧化应激增加、TOPK 磷酸化减少以及 PTEN/PI3K/Akt 信号通路受损。此外，TOPK 过表达恢复了高葡萄糖中暴露的 H9c2 细胞的缺氧后 p-PTEN 和 p-Akt，并减少了细胞死亡和氧化应激，而这种作用被 PI3K/Akt 抑制所阻断。总之，SPostC 可能通过 TOPK 介导的 PTEN/PI3K/Akt 激活来防止心肌缺血/再灌注损伤，而这种信号通路的激活受损可能是 SPostC 在糖尿病中丧失心脏保护作用的原因。
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