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Comparative Study
. 2016 Feb;100(2):365-72.
doi: 10.1097/TP.0000000000001032.

The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury (V体育安卓版)

Haomming Zhou  1 , Jianjun Zhu, Shi Yue, Ling Lu, Ronald W Busuttil, Jerzy W Kupiec-Weglinski, Xuehao Wang, Yuan Zhai
Affiliations
Comparative Study

"VSports注册入口" The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury

Haomming Zhou et al. Transplantation. 2016 Feb.

V体育官网 - Abstract

Endoplasmic reticulum (ER) stress plays critical roles in the pathogenesis of liver ischemia-reperfusion injury (IRI) VSports手机版. As ER stress triggers an adaptive cellular response, the question of what determines its functional outcome in liver IRI remains to be defined. In a murine liver partial warm ischemia model, we studied how transient (30 minutes) or prolonged (90 minutes) liver ischemia regulated local ER stress response and autophagy activities and their relationship with liver IRI. Effects of chemical chaperon 4-phenylbutyrate (4-PBA) or autophagy inhibitor 3-methyladenine (3-MA) were evaluated. Our results showed that although the activating transcription factor 6 branch of ER stress response was induced in livers by both types of ischemia, liver autophagy was activated by transient, but inhibited by prolonged, ischemia. Although 3-MA had no effects on liver IRI after prolonged ischemia, it significantly increased liver IRI after transient ischemia. The 4-PBA treatment protected livers from IRI after prolonged ischemia by restoring autophagy flux, and the adjunctive 3-MA treatment abrogated its liver protective effect. The same 4-PBA treatment, however, increased liver IRI and disrupted autophagy flux after transient ischemia. Although both types of ischemia activated 5' adenosine monophosphate-activated protein kinase and inactivated protein kinase B (Akt), prolonged ischemia also resulted in downregulations of autophagy-related gene 3 and autophagy-related gene 5 in ischemic livers. These results indicate a functional dichotomy of ER stress response in liver IRI via its regulation of autophagy. Transient ischemia activates autophagy to protect livers from IRI, whereas prolonged ischemia inhibits autophagy to promote the development of liver IRI. .

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Conflict of interest statement

Disclosures: All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Western blot analysis of liver autophagy flux and UPR response against IR. Liver tissues were harvested after either 30m or 90m ischemia and 0h or 1h of reperfusion. Activation of liver UPR response by IR was determined by Western blot analysis of cleaved ATF6, ATF4 and spliced XBP-1 at 0h post reperfusion (A). Average ratios of UPR signaling molecules/β-actin were plotted (B). To measure autophagy flux, separate groups of mice were received either vehicle or CQ treatment (60mg/kg, i.p. at −1h), as described in the Material and Methods. Represented LC3B II and β-actin Western blots were shown (C). Average ratios of LC3B II/β-actin in the presence and absence of CQ were calculated and plotted (D). Representative results of at least 2 different experiments. n=2–3/group. *p<0.05.
Figure 2
Figure 2
Dichotomy of ER stress in liver IRI. 4-PBA (100 mg/kg, i.p. at −2h) was administered in different groups of mice prior to the onset of either transient (I30) or prolonged (I90) liver ischemia, as described in the Materials and Methods. Liver IRI was evaluated at 6h post reperfusion (R6h). Average sALT levels of different experimental groups were plotted (A. n=4mice/group), as well as representative liver histology (H/E, B, x100, Scale bars indicate 100μM) with Suzuki scores (C). Representative results of 2 different experiments. n=3–4/group. *p<0.05.
Figure 3
Figure 3
ER stress regulation of autophagy in liver IRI. 4-PBA (100 mg/kg, i.p. at −2h) was administered with or without CQ (60mg/kg, i.p. at −1h) in different groups of mice prior to the onset of either transient (I30) or prolonged (I90) liver ischemia, as described in the Materials and Methods. Ischemic liver tissues were harvested at 1h post reperfusion. Western blots of ATF6 (A, B) and LC3B-II (C, D, E, F), as well as their calculated ratios vs. β-actin in different experimental groups were shown. Representative results of 2 different experiments. n=3–4/group. *p<0.05.
Figure 4
Figure 4
Autophagy regulation of liver IRI. 3-MA (30mg/kg, i.p. at −1h) or PBS (vehicle control) was administered into mice prior to the onset of liver ischemia, as described in the Materials and Methods. Treated mice were subjected to 30m or 90m ischemia followed by 6h of reperfusion. Average sALT levels of different experimental groups were plotted (A), as well as representative liver histology (H/E, B, x100, Scale bars indicate 100μM) with Suzuki scores (C). Representative Western blot of liver LC3B-II was shown (D). Ratios of LC3B-II/β-actin were calculated and plotted (E). Representative results of at least 2 different experiments. n=3–4/group. *p<0.05.
Figure 5
Figure 5
Autophagy is required for 4-PBA protection of livers from IRI. 4-PBA (100 mg/kg, i.p. at −2h) was administered with or without 3-MA (30mg/kg, i.p. at −1h) in different groups of mice prior to the onset of prolonged liver ischemia. Liver IRI was evaluated at 6h post reperfusion. Average sALT levels of different experimental groups were plotted (A), as well as representative liver histology (B, H/E, x100, Scale bars indicate 100μM) with Suzuki scores (C). Representative results of 2 different experiments. n=3–4/group. *p<0.05.
Figure 6
Figure 6
Autophagy signaling pathways and machinery proteins in liver IRI. Liver tissues were harvested after either 30m or 90m ischemia and 0h or 1h of reperfusion. (A) Representative Western blots of phosphorylated Akt (at Thr308 and Ser473), phosphorylated AMPK (Thr172), and β-actin (at 0h post reperfusion) were shown. (B) Average ratios of p-Akt and p-AMPK vs. β-actin were plotted. (C) Representative Western blots of Atg3, Atg5, Beclin-1 and β-actin (at 0h and 1h post reperfusion) were shown. (D) Average ratios of Atg3, or Atg5, or Beclin-1 vs. β-actin were plotted. Representative results of 2 different experiments. n=3–4/group. *p<0.05.
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References

    1. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–529. - PubMed (VSports手机版)
    1. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102. - PubMed
    1. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002;110(10):1389–1398. - "V体育平台登录" PMC - PubMed
    1. Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology. 2011;53(5):1752–1763. - PMC - PubMed
    1. Bailly-Maitre B, Fondevila C, Kaldas F, et al. Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2006;103(8):2809–2814. - PMC - PubMed

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