Abstract
Previous studies from our group have demonstrated that sevoflurane post-conditioning (SPC) protects against myocardial ischemia reperfusion injury via elevating the intranuclear expression of hypoxia inducible factor-1 alpha (HIF-1α). However, diabetic SPC is associated with decreased myocardial protection and disruption of the HIF-1 signaling pathway. Previous studies have demonstrated that cobalt chloride (CoCl2) can upregulate HIF-1α expression under diabetic conditions, but whether myocardial protection by SPC can be restored afterward remains unclear. We established a rat model of type 2 diabetes and a Langendorff isolated heart model of ischemia-reperfusion injury. Prior to reperfusion, 2.4% sevoflurane was used as a post-conditioning treatment. The diabetic rats were treated with CoCl2 24 h before the experiment. At the end of reperfusion, tests were performed to assess myocardial function, infarct size, mitochondrial morphology, nitric oxide (NO), Mitochondrial reactive oxygen species (ROS), mitochondrial respiratory function and enzyme activity, HIF-1α, vascular endothelial growth factor (VEGF) and endothelial NO synthase (eNOS) protein levels. In addition, myocardial protection by SPC was monitored after the blood glucose levels were lowered by insulin. The diabetic state was associated with deficient SPC protection and decreased HIF-1α expression. After treating the diabetic rats with CoCl2, SPC significantly upregulated the expression of HIF-1α, VEGF and eNOS, which markedly improved cardiac function, NO, mitochondrial respiratory function, and enzyme activity and decreased the infarction areas and ROS. In addition, these effects were not influenced by blood glucose levels. This study proved that CoCl2activates the HIF-1α signaling pathway, which restores SPC-dependent myocardial protection under diabetic conditions, and the protective effects of SPC were independent of blood glucose levels.
Highlights
Diabetes is an independent risk factor for perioperative complications and death associated with cardiovascular diseases, and the occurrence of myocardial ischemia is 1.45- to 2.99fold higher in diabetic than in non-diabetic individuals (Whiting et al, 2011; Yeh et al, 2013)
This study demonstrated that under non-diabetic conditions, sevoflurane post-conditioning (SPC)-dependent myocardial protection is associated with the upregulation of both HIF-1α and its downstream mediators vascular endothelial growth factor (VEGF) and endothelial NO synthase (eNOS)
HIF-1α signaling is impaired under diabetic conditions, and this leads to the loss of SPC-dependent myocardial protection
Summary
Diabetes is an independent risk factor for perioperative complications and death associated with cardiovascular diseases, and the occurrence of myocardial ischemia is 1.45- to 2.99fold higher in diabetic than in non-diabetic individuals (Whiting et al, 2011; Yeh et al, 2013). The diabetic state can interfere with the intrinsic protection mechanisms of ischemic preconditioning and post-conditioning during the reperfusion period, thereby increasing the myocardial infarction area (Ebel et al, 2003; Inamura et al, 2010). Studies have demonstrated that sevoflurane post-conditioning (SPC) has protective effects on the myocardium of nondiabetic patients that resemble ischemic preconditioning, and this is a commonly used perioperative measure to avoid myocardial ischemia-reperfusion injury (Zhang et al, 2014; Cao et al, 2015; Yu et al, 2015). It has been reported that under diabetic conditions, the hypoxia-inducible factor-1alpha (HIF-1α) signaling pathway is damaged (Heather and Clarke, 2011; Xiao et al, 2013). We examined whether the loss of SPC-induced myocardial protection under diabetic conditions was associated with defects in the HIF-1 signaling pathway
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