Abstract
Mitochondrial autophagy is involved in myocardial protection of sevoflurane postconditioning (SPostC) and in diabetic state this protective effect is weakened due to impaired HIF-1 signaling pathway. Previous studies have proved that deferoxamine (DFO) could activate impaired HIF-1α in diabetic state to restore the cardioprotective of sevoflurane, while the specific mechanism is unclear. This study aims to investigate whether HIF-1/BNIP3-mediated mitochondrial autophagy is involved in the restoration of sevoflurane postconditioning cardioprotection in diabetic state. Ischemia/reperfusion (I/R) model was established by ligating the anterior descending coronary artery and sevoflurane was administered at the first 15 min of reperfusion. Myocardial infarct size, mitochondrial ultrastructure and autophagosome, ATP content, mitochondrial membrane potential, ROS production, HIF-1α, BNIP3, LC3B-II, Beclin-1, P62, LAMP2 protein expression were detected 2 h after reperfusion, and cardiac function was evaluated by ultrasound at 24 h after reperfusion. Our results showed that with DFO treatment, SPostC up-regulated the expression of HIF-1α and BNIP3, thus reduced the expression of key autophagy proteins LC3B-II, Beclin-1, p62, and increased the expression of LAMP2. Furthermore, it reduced the accumulation of autophagosomes and ROS production, increased the content of ATP, and stabilized the membrane potential. Finally, the myocardial infarction size was reduced and cardiac function was improved. Taken together, DFO treatment combined with SPostC could alleviate myocardial ischemia reperfusion injury in diabetic rats by restoring and promoting HIF-1/BNIP3-mediated mitochondrial autophagy.
Highlights
Cardiovascular disease (CVD) is a globally prominent social medical problem, and the prevalence rate is rising and becoming the leading cause of death worldwide
The purpose of this study was to determine the effect of DFO treatment combined with sevoflurane postconditioning (SPostC) on mitochondrial autophagy, and to verify that restoration of HIF-1a/BNIP3-mediated mitochondrial autophagy in diabetic state is the key to restore the protective effect of SPostC
We further examined the protein expression of HIF-1a, BNIP3, LC3BII, P62, Beclin-1, LAMP2, and there is no significant difference between SPostC group and I/R group (P > 0.05 Figures 8A–F)
Summary
Cardiovascular disease (CVD) is a globally prominent social medical problem, and the prevalence rate is rising and becoming the leading cause of death worldwide (van der Ende et al, 2017). How to alleviate perioperative myocardial ischemia reperfusion injury of diabetics mellitus is a multidisciplinary problem need to be urgently solved. Many studies have confirmed that sevoflurane postconditioning (SPostC) can alleviate ischemia-reperfusion injury effectively in healthy myocardium (Yu et al, 2015; Wu et al, 2017b; Qiao et al, 2019). 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)
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