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Abstract
Direct peritoneal resuscitation with pyruvate (Pyr-PDS) has emerged as an interesting candidate to alleviate injury in diverse organs, while the potential mechanism has yet to be fully elucidated. To explore the effect of autophagy in the spinal cord ischemia-reperfusion (SCIR) injury and the underlying mechanism, we established a model of SCIR in vivo and in vitro. In vivo, male SD rats underwent aortic occlusion for 60 min and then followed by intraperitoneally infused with 20 mL of pyruvate or normal saline for 30 min, and the spinal cords were removed for analysis after 48 h of reperfusion. The functional and morphological results showed that Pyr-PDS alleviated SCIR injury; meanwhile, the expression of autophagy-related genes and transmission electron microscopy displayed autophagy was activated by SCIR injury, and Pyr-PDS treatment could further upregulate the degree of autophagy which plays a protective part in the SCIR injury, while there is no significant difference after treatment with saline. In addition, SCIR injury inhibited expression of PHD2, which results to activate its downstream HIF-1α/BNIP3 pathway to promote autophagy. In the Pyr-PDS, the results revealed PHD2 was further inhibited compared to the SCIR group, which could further activate the HIF-1α/BNIP3 signaling pathway. Additionally, oxygen-glucose deprivation and reoxygenation were applied to SH-SY5Y cells to mimic anoxic conditions in vitro, and the expression of autophagy-related genes, PHD2, and its downstream HIF-1α/BNIP3 pathway showed the same trend as the results in vivo. Besides, IOX2, a specific inhibitor of PHD2 was also treated to SH-SY5Y cells during reoxygenation, in which the result is as same as the pyruvate group. Then, we observed the expression of autophagy-related genes and the HIF-1α signal pathway in the process of reoxygenation; the results showed that as the reoxygenation goes, the expression of the HIF-1α signal pathway and degree of autophagy came to decrease gradually, while treated with pyruvate could maintain autophagy high and stable through keeping PHD2 at a lower level during reoxygenation, and the latter was observed downregulated during reoxygenation process from 0 to 24 hours in a time-effect way. The above results indicated that direct peritoneal resuscitation with pyruvate showed effective protection to ischemia-reperfusion of the spinal cord through activating autophagy via acting on PHD2 and its downstream HIF-1α/BNIP3 pathway.
Highlights
Thoracoabdominal surgery is accompanied with blockage of blood flow to the aorta, which causes spinal cord ischemiareperfusion (SCIR) injury, and the latter is a dreaded complication which poses an important challenge to lower the risks of destructive paraplegia and paralysis with high disability rate [1]; the potential mechanism of SCIR injury has lately received great attention [2,3,4]
Our research explored the effect of the HIF-1α/Bnip3 signaling pathway in regulating autophagy induced by SCIR
The results indicated that the HIF-1α/Bnip3 pathway was activated to upregulate the degree of autophagy after OGD in vitro, while the process of reperfusion reversed the activation of the HIF-1α/Bnip3 signal pathway, which could be increased again by pyruvate treatment
Summary
Thoracoabdominal surgery is accompanied with blockage of blood flow to the aorta, which causes spinal cord ischemiareperfusion (SCIR) injury, and the latter is a dreaded complication which poses an important challenge to lower the risks of destructive paraplegia and paralysis with high disability rate [1]; the potential mechanism of SCIR injury has lately received great attention [2,3,4]. It has been proved that autophagy is of great importance in the SCIR injury; it has yet to be identified the effect of autophagy in the development of SCIR injury [7,8,9]. The intensity and duration of autophagy process are regulated by a variety of autophagy-related proteins such as p62, Beclin-1, and mTOR (mammalian target of rapamycin). Studies have shown that Beclin-1 and mTOR are the downstream of Bcl2/adenovirus EIB19 kDa-interacting protein 3 (BNIP3) which could regulate the extent degree of autophagy in a variety of cells [10, 11]
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