Inactivation of TOPK Caused by Hyperglycemia Blocks Diabetic Heart Sensitivity to Sevoflurane Postconditioning by Impairing the PTEN/PI3K/Akt Signaling

Abstract

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.

Cadmium and molybdenum co-induce pyroptosis and apoptosis via the PTEN/PI3K/AKT axis in the livers of Shaoxing ducks (Anas platyrhynchos)

“…It is well known that the PTEN/PI3K/AKT axis can regulate cell behaviors, and act as a protective axis for cell survival. 68,69 As a non-redundant, plasma-membrane lipid phosphatase, PTEN is a PI3K inhibitor which can suppress the downstream protein kinases, such as AKT and 3-phosphoinositide dependent kinase1 (PDK1). 70,71 PTEN is involved in many processes, such as cell proliferation, apoptosis, pyroptosis, autophagy, etc.…”

The Protective Effect of Sevoflurane Conditionings Against Myocardial Ischemia/Reperfusion Injury: A Systematic Review and Meta-Analysis of Preclinical Trials in in-vivo Models

“…Eventually, 39 articles were further excluded; of them, 12 articles were due to difference of study protocols, 11 articles had TTC staining only, 6 articles were ex-vivo studies, 5 articles did not report infarct size, 2 articles were no sample size per group, 2 articles could not acquire full text, and 1 article used animal model with the risk factors of cardiovascular diseases ( Figure 1 ). As a result, 37 literatures [(14 SPreC studies ( 10 , 17 , 19 , 21 , 22 , 24 – 32 ), 20 SPostC studies ( 11 , 33 – 51 ), and 3 both the SPreC and SPostC studies ( 18 , 20 , 23 )] met our selection criteria and were included in the analysis. Of 37 included studies, 7 studies provided the associated information of infarct size merely in figures, including 3 SPreC studies ( 10 , 30 , 31 ) and 4 SPostC studies ( 37 , 45 , 49 , 50 ).…”

Novel oral edaravone attenuates diastolic dysfunction of diabetic cardiomyopathy by activating the Nrf2 signaling pathway

“…Our study con rmed that OED can attenuate the diabetic cardiomyopathy possibly via activating Nrf2 pathway. However, researches have reported that Nrf2 activation may depend on evaluating the upstream signaling pathways, such as PI3K 59 , β-RECP 60 , SIRT1 61 and GSKβ 54 . It requires experimental validation that whether OED activates the upstream signaling pathways to further affect Nrf2 or not.…”