Abstract
Hypoxic preconditioning (HPC) exerts a protective effect against hypoxic/ischemic brain injury, and one mechanism explaining this effect may involve the upregulation of hypoxia-inducible factor-1 (HIF-1). Autophagy, an endogenous protective mechanism against hypoxic/ischemic injury, is correlated with the activation of the HIF-1α/Beclin1 signaling pathway. Based on previous studies, we hypothesize that the protective role of HPC may involve autophagy occurring via activation of the HIF-1α/Beclin1 signaling pathway. To test this hypothesis, we evaluated the effects of HPC on oxygen-glucose deprivation/reperfusion (OGD/R)-induced apoptosis and autophagy in SH-SY5Y cells. HPC significantly attenuated OGD/R-induced apoptosis, and this effect was suppressed by the autophagy inhibitor 3-methyladenine and mimicked by the autophagy agonist rapamycin. In control SH-SY5Y cells, HPC upregulated the expression of HIF-1α and downstream molecules such as BNIP3 and Beclin1. Additionally, HPC increased the LC3-II/LC3-I ratio and decreased p62 levels. The increase in the LC3-II/LC3-I ratio was inhibited by the HIF-1α inhibitor YC-1 or by Beclin1-short hairpin RNA (shRNA). In OGD/R-treated SH-SY5Y cells, HPC also upregulated the expression levels of HIF-1α, BNIP3, and Beclin1, as well as the LC3-II/LC3-I ratio. Furthermore, YC-1 or Beclin1-shRNA attenuated the HPC-mediated cell viability in OGD/R-treated cells. Taken together, our results demonstrate that HPC protects SH-SY5Y cells against OGD/R via HIF-1α/Beclin1-regulated autophagy.
Highlights
Cerebrovascular diseases, such as stroke, have a high incidence of morbidity and mortality
Our results demonstrate that Hypoxic preconditioning (HPC) protects SH-SY5Y cells against oxygen-glucose deprivation/reperfusion (OGD/R) via HIF-1α/Beclin1-regulated autophagy
Beclin1 is a well-known key regulator of autophagy; this protein controls the autophagic process by regulating class III Phosphatidylinositol 3-kinase (PI3K)-dependent generation of phosphatidylinositol 3-phosphate (PI3P) and the subsequent recruitment of additional autophagy-associated (ATG) proteins that promote autophagosome formation (Wirawan et al 2012), which plays an essential role in autophagy activation (Maejima et al 2016; Sinha and Levine 2008)
Summary
Cerebrovascular diseases, such as stroke, have a high incidence of morbidity and mortality. Phosphatidylinositol 3-kinase (PI3K) is a key regulator of autophagy, as it plays an important role in many biological processes, including controlling the activation of mTOR. Beclin is a well-known key regulator of autophagy; this protein controls the autophagic process by regulating class III PI3K-dependent generation of phosphatidylinositol 3-phosphate (PI3P) and the subsequent recruitment of additional autophagy-associated (ATG) proteins that promote autophagosome formation (Wirawan et al 2012), which plays an essential role in autophagy activation (Maejima et al 2016; Sinha and Levine 2008). We adapted an oxygen-glucose deprivation/reperfusion (OGD/R) model in SH-SY5Y cells and determined whether the HIF-1α/Beclin signaling pathway modulates autophagy and whether such regulation contributes to HPC-induced protection against OGD/R
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