Abstract
Intermittent hypoxia (IH), characterized as cyclic episodes of short-period hypoxia followed by normoxia, occurs in many physiological and pathophysiological conditions such as pregnancy, athlete, obstructive sleep apnea, and asthma. Hypoxia can induce autophagy, which is activated in response to protein aggregates, in the proteotoxic forms of cardiac diseases. Previous studies suggested that autophagy can protect cells by avoiding accumulation of misfolded proteins, which can be generated in response to ischemia/reperfusion (I/R) injury. The objective of the present study was to determine whether IH-induced autophagy can attenuate endoplasmic reticulum (ER) stress and cell death. In this study, H9c2 cell line, rat primary cultured cardiomyocytes, and C57BL/6 male mice underwent IH with an oscillating O2 concentration between 4 and 20% every 30 min for 1–4 days in an incubator. The levels of LC3, an autophagy indicator protein and CHOP and GRP78 (ER stress-related proteins) were measured by Western blotting analyses. Our data demonstrated that the autophagy-related proteins were upregulated in days 1–3, while the ER stress-related proteins were downregulated on the second day after IH. Treatment with H2O2 (100 μM) for 24 h caused ER stress and increased the level of ER stress-related proteins, and these effects were abolished by pre-treatment with IH condition. In response to the autophagy inhibitor, the level of ER stress-related proteins was upregulated again. Taken together, our data suggested that IH could increase myocardial autophagy as an adaptive response to prevent the ER stress and apoptosis.
Highlights
The endoplasmic reticulum (ER), which possesses the structural and functional features of an organelle, supports the regulation of synthesis, folding, and orderly transport of proteins (Gorlach et al, 2006)
The effect of intermittent hypoxia (IH) on the levels of H2O2-increased ER stress-related proteins was significantly reduced by 3MA, CQ, or Wort (Figures 5A–E), except for the cleaved activating transcription factor 6 (ATF6) (Figure 5E). These results suggest that inhibiting the elF2, ATF4, or inositol-requiring protein 1 (IRE1) signaling pathway might contribute to the autophagy-reduced ER stress
The results showed that the levels of cleaved poly(ADP-ribose) polymerase-1 (PARP) were not significantly different between room air (RA) treated with and without the autophagy inhibitors, except that Wort treatment significantly reduced the level of cleaved PARA (Figures 6A,B)
Summary
The endoplasmic reticulum (ER), which possesses the structural and functional features of an organelle, supports the regulation of synthesis, folding, and orderly transport of proteins (Gorlach et al, 2006). Disruption of ER functions can induce an accumulation of unfolded and misfolded proteins in the ER lumen, a condition known as ER stress. Chronic or prolonged ER stress can trigger apoptosis (Toth et al, 2007). Cells initiate unfolded protein responses (UPRs) including protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6), three major proteins on the ER membrane to alleviate the disturbance of ER homeostasis (Ivanova and Orekhov, 2016). ER has been indicated to play a major role in adaptive responses to I/R-caused injury. It has been demonstrated that chronic IH could activate ER stress, subsequently causing cardiomyocytic apoptosis (Xu et al, 2015). Roles of ER responses in mediating pathophysiological reactions in IH are still not well known
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