Cobalt Chloride Upregulates Impaired HIF-1α Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats

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.

Deferoxamine Treatment Combined With Sevoflurane Postconditioning Attenuates Myocardial Ischemia-Reperfusion Injury by Restoring HIF-1/BNIP3-Mediated Mitochondrial Autophagy in GK Rats

“…Our previous studies have confirmed that cobalt chloride or deferoxamine can reverse the impaired HIF-1a in diabetic state and restore the protective effect of SPostC (Wu et al, 2017a;Xie et al, 2017). Although the specific molecular mechanism is still unclear, we found that myocardial energy metabolism disorder is the key to the decline of diabetic myocardium against I/R injury and increased vulnerability, while functional integrity of mitochondria are the source of sufficient myocardial motility.…”

“…Our previous study found that HIF-1a is an endogenous target that mediates the protective effects of sevoflurane postconditioning , but inactivated in diabetic state (Thangarajah et al, 2010;Bento and Pereira, 2011). Therefore, it is proposed that impaired HIF-1a is the reason causing SPostC protection weakening in diabetic state, and in animal experiments it is proved by our research group that cobalt chloride or deferoxamine reversed the impaired HIF-1a and restored the protection of sevoflurane postconditioning (Wu et al, 2017a;Xie et al, 2017).…”

Pharmacological postconditioning: a molecular aspect in ischemic injury

“…Before 120 mins of reperfusion and after 40 min of global ischaemia, 2.4% of sevoflurane was administered as the PoCo agent in diabetic rats which resulted in upregulation of the expression of HIF‐1a, VEGF and eNOS, which highly improved cardiac function, NO, mitochondrial respiratory function and enzyme activity and decreased the infarction areas and ROS. [ 120 ]…”

Commentary: Neutral Commentary on Frontiers Article “Cobalt Chloride Upregulates Impaired HIF-1α Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats”

“…These reports validate the significance of HIF-1α in conditioning via stabilization of HIF-1α (Zhao et al, 2010 ). The current manuscript titled,” Cobalt Chloride Upregulates Impaired HIF-1-alpha Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats “ by Wu et al, in the journal Frontiers Physiology, 2017 June 13;8:395, further investigates the scope of HIF-1α signaling in the cardioprotective sevoflurane signaling against IR injury in the diabetic heart (Wu et al, 2017 ).…”

“…The current study by Wu et al, investigates the role sevoflurane as a post-conditioning mechanism against IR injury in a diabetic rat model (Wu et al, 2017 ). The cardioprotective signaling mechanism offered by the investigators determines that sevoflurane promotes stabilization of HIF-1α resulting in mitigating IR injury.…”