Aggravated intestinal ischemia‑reperfusion injury is associated with activated mitochondrial autophagy in a mouse model of diabetes

Zeng,Zi; Liu,Hui‑Min; Zhang,Yun‑Yan; Chen,Rong; Sun,Tao; Li,Wei; Sun,Qian; Xia,Zhong‑Yuan; Meng,Qing‑Tao

doi:10.3892/mmr.2020.11270

Aggravated intestinal ischemia‑reperfusion injury is associated with activated mitochondrial autophagy in a mouse model of diabetes

Authors:
- Zi Zeng
- Hui‑Min Liu
- Yun‑Yan Zhang
- Rong Chen
- Tao Sun
- Wei Li
- Qian Sun
- Zhong‑Yuan Xia
- Qing‑Tao Meng
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Affiliations: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: June 24, 2020 https://doi.org/10.3892/mmr.2020.11270
Pages: 1892-1900
Copyright: © Zeng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Numerous studies have reported that diabetes is associated with an increased susceptibility to cardiac ischemia‑ reperfusion injury; however, the mechanism underlying the role of diabetes during intestinal ischemia‑reperfusion (IIR) has yet to be elucidated. The present study evaluated the intestinal pathological alterations and possible underlying mechanisms in a mouse model of type 1 diabetes mellitus with IIR. The effects of diabetes were investigated by assessing the histopathology, oxidative stress, inflammatory cytokine levels in intestine tissues and blood plasma, and protein expression levels of phosphatase and tensin homolog‑induced putative kinase (PINK1), Parkin and the ratio of light chain 3B (LC3B) II/I. The results demonstrated that diabetes increased the Chiu's intestinal injury score, concentration of interleukin (IL)‑1β, IL‑6 and tumor necrosis factor (TNF)‑α, and levels of oxidative stress. Furthermore, the alterations were more pronounced in the diabetes with IIR group. The expression levels of PINK1 and Parkin, as well as the ratio of LC3BII/I, were significantly upregulated in the IIR group compared with the Sham group. Diabetes activated PINK1 and Parkin, and increased the expression of LC3BII. Furthermore, transmission electron microscopy revealed that mitochondrial destruction and the number of autophagosomes was increased in the diabetic groups compared with the non‑diabetic groups. Collectively, the results of the present study suggest that diabetes increased intestinal vulnerability to IIR by enhancing inflammation and oxidative stress. Furthermore, IIR was associated with overactivation of mitochondrial autophagy; therefore, the increased vulnerability to IIR‑induced intestine damage due to diabetes may be associated with PINK1/Parkin‑regulated mitochondrial autophagy.

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1	Miki T, Itoh T, Sunaga D and Miura T: Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning. Cardiovasc Diabetol. 11:672012. View Article : Google Scholar : PubMed/NCBI
2	Giacco F and Brownlee M: Oxidative stress and diabetic complications. Circ Res. 107:1058–1070. 2010. View Article : Google Scholar : PubMed/NCBI
3	D'Addio F and Fiorina P: Type 1 diabetes and dysfunctional intestinal homeostasis. Trends Endocrinol Metab. 27:493–503. 2016. View Article : Google Scholar : PubMed/NCBI
4	Nankervis CA, Giannone PJ and Reber KM: The neonatal intestinal vasculature: Contributing factors to necrotizing enterocolitis. Semin Perinatol. 32:83–91. 2008. View Article : Google Scholar : PubMed/NCBI
5	Yasuhara H: Acute mesenteric ischemia: The challenge of gastroenterology. Surg Today. 35:185–195. 2005. View Article : Google Scholar : PubMed/NCBI
6	Schwartz MZ: Novel therapies for the management of short bowel syndrome in children. Pediatr Surg Int. 29:967–974. 2013. View Article : Google Scholar : PubMed/NCBI
7	Posma LA, Bleichrodt RP, Lomme RM, de Man BM, van Goor H and Hendriks T: Early anastomotic repair in the rat intestine is affected by transient preoperative mesenteric ischemia. J Gastrointest Surg. 13:1099–1106. 2009. View Article : Google Scholar : PubMed/NCBI
8	Corcos O and Nuzzo A: Gastro-intestinal vascular emergencies. Best Pract Res Clin Gastroenterol. 27:709–725. 2013. View Article : Google Scholar : PubMed/NCBI
9	Fishman JE, Sheth SU, Levy G, Alli V, Lu Q, Xu D, Qin Y, Qin X and Deitch EA: Intraluminal nonbacterial intestinal components control gut and lung injury following trauma-hemorrhagic shock. Ann Surg. 260:1112–1120. 2014. View Article : Google Scholar : PubMed/NCBI
10	Sastry P, Hardman G, Page A, Parker R, Goddard M, Large S and Jenkins DP: Mesenteric ischaemia following cardiac surgery: The influence of intraoperative perfusion parameters. Interact Cardiovasc Thorac Surg. 19:419–424. 2014. View Article : Google Scholar : PubMed/NCBI
11	Hart ML, Gorzolla IC, Schittenhelm J, Dalton JH and Eltzschig HK: Retraction: Hypoxia-inducible factor-1α-dependent protection from intestinal ischemia/reperfusion injury involves Ecto-5′-nucleotidase (CD73) and the A2B adenosine receptor. J Immunol. 199:19422017. View Article : Google Scholar : PubMed/NCBI
12	Puleo F, Arvanitakis M, Van Gossum A and Preiser JC: Gut failure in the ICU. Semin Respir Crit Care Med. 32:626–638. 2011. View Article : Google Scholar : PubMed/NCBI
13	Zhao W, Gan X, Su G, Wanling G, Li S, Hei Z, Yang C and Wang H: The interaction between oxidative stress and mast cell activation plays a role in acute lung injuries induced by intestinal ischemia-reperfusion. J Surg Res. 187:542–552. 2014. View Article : Google Scholar : PubMed/NCBI
14	Daniel RA, Cardoso VK, Góis JE Jr, Parra RS, Garcia SB, Rocha JJ and Féres O: Effect of hyperbaric oxygen therapy on the intestinal ischemia reperfusion injury. Acta Cir Bras. 26:463–469. 2011. View Article : Google Scholar : PubMed/NCBI
15	Liu L, Tan Q, Hu B, Wu H, Wang C, Liu R and Tang C: Somatostatin Improved B cells mature in macaques during intestinal ischemia-reperfusion. PLoS One. 10:e01336922015. View Article : Google Scholar : PubMed/NCBI
16	Wu H, Deng YY, Liu L, Tan QH, Wang CH, Guo MM, Xie YM and Tang CW: Intestinal ischemia-reperfusion of macaques triggers a strong innate immune response. World J Gastroenterol. 20:15327–15334. 2014. View Article : Google Scholar : PubMed/NCBI
17	Whittington HJ, Babu GG, Mocanu MM, Yellon DM and Hausenloy DJ: The diabetic heart: Too sweet for its own good? Cardiol Res Pract. 2012:8456982012. View Article : Google Scholar : PubMed/NCBI
18	Ansley DM and Baohua W: Oxidative stress and myocardial injury in the diabetic heart. J Pathol. 229:232–241. 2013. View Article : Google Scholar : PubMed/NCBI
19	Takayanagi R, Inoguchi T and Ohnaka K: Clinical and experimental evidence for oxidative stress as an exacerbating factor of diabetes mellitus. J Clin Biochem Nutr. 48:72–77. 2011. View Article : Google Scholar : PubMed/NCBI
20	Zhang P, Li T, Wu X, Nice EC, Huang C and Zhang Y: Oxidative stress and diabetes: Antioxidative strategies. Front Med. Apr 4–2020.(Epub ahead of print). View Article : Google Scholar
21	Lenaz G, Bovina C, D'Aurelio M, Fato R, Formiggini G, Genova ML, Giuliano G, Merlo Pich M, Paolucci U, Parenti Castelli G and Ventura B: Role of mitochondria in oxidative stress and aging. Ann NY Acad Sci. 959:199–213. 2002. View Article : Google Scholar : PubMed/NCBI
22	Zorov DB, Juhaszova M and Sollott SJ: Mitochondrial ROS-induced ROS release: An update and review. Biochim Biophys Acta. 1757:509–517. 2006. View Article : Google Scholar : PubMed/NCBI
23	Tumurkhuu G, Koide N, Dagvadorj J, Morikawa A, Hassan F, Islam S, Naiki Y, Mori I, Yoshida T and Yokochi T: The mechanism of development of acute lung injury in lethal endotoxic shock using alpha-galactosylceramide sensitization. Clin Exp Immunol. 152:182–191. 2008. View Article : Google Scholar : PubMed/NCBI
24	Shen X, Zheng S, Metreveli NS and Epstein PN: Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes. 55:798–805. 2006. View Article : Google Scholar : PubMed/NCBI
25	Sack MN: Type 2 diabetes, mitochondrial biology and the heart. J Mol Cell Cardiol. 46:842–849. 2009. View Article : Google Scholar : PubMed/NCBI
26	Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature. 414:813–820. 2001. View Article : Google Scholar : PubMed/NCBI
27	Wang S, Wang C, Yan F, Wang T, He Y, Li H, Xia Z and Zhang Z: N-Acetylcysteine attenuates diabetic myocardial ischemia reperfusion injury through inhibiting excessive autophagy. Mediators Inflamm. 2017:92572912017. View Article : Google Scholar : PubMed/NCBI
28	International C: Guide for the care and use of laboratory animals. Publication. 327:963–965. 2011.
29	Meng QT, Cao C, Wu Y, Liu HM, Li W, Sun Q, Chen R, Xiao YG, Tang LH, Jiang Y, et al: Ischemic post-conditioning attenuates acute lung injury induced by intestinal ischemia-reperfusion in mice: Role of Nrf2. Lab Invest. 96:1087–1104. 2016. View Article : Google Scholar : PubMed/NCBI
30	Yu C, Tan S, Zhou C, Zhu C, Kang X, Liu S, Zhao S, Fan S, Yu Z, Peng A and Wang Z: Berberine reduces uremia-associated intestinal mucosal barrier damage. Biol Pharm Bull. 39:1787–1792. 2016. View Article : Google Scholar : PubMed/NCBI
31	Misra HP and Fridovich I: The role of superoxide anion in the autoxidation of epinephrine and simple assay for superoxide dismutase. J Biol Chem. 247:3170–3175. 1972.PubMed/NCBI
32	Crane JD, Devries MC, Safdar A, Hamadeh MJ and Tarnopolsky MA: The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol A Biol Sci Med Sci. 65:119–128. 2010. View Article : Google Scholar : PubMed/NCBI
33	Swank GM and Deitch EA: Role of the gut in multiple organ failure: Bacterial translocation and permeability changes. World J Surg. 20:411–417. 1996. View Article : Google Scholar : PubMed/NCBI
34	Gonzalez LM, Moeser AJ and Blikslager AT: Animal models of ischemia-reperfusion-induced intestinal injury: Progress and promise for translational research. Am J Physiol Gastrointest Liver Physiol. 308:G63–G75. 2015. View Article : Google Scholar : PubMed/NCBI
35	Simos Y, Karkabounas S, Verginadis I, Charalampidis P, Filiou D, Charalabopoulos K, Zioris I, Kalfakakou V and Evangellou A: Intra-peritoneal application of catechins and EGCG as in vivo inhibitors of ozone-induced oxidative stress. Phytomedicine. 18:579–585. 2011. View Article : Google Scholar : PubMed/NCBI
36	Zu G, Guo J, Che N, Zhou T, Zhang X, Wang G, Ji A and Tian X: Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway. Sci Rep. 6:384802016. View Article : Google Scholar : PubMed/NCBI
37	Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, et al: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 404:787–790. 2000. View Article : Google Scholar : PubMed/NCBI
38	Wen Z, Hou W, Wu W, Zhao Y, Dong X, Bai X, Peng L and Song L: 6′-O-Galloylpaeoniflorin attenuates cerebral ischemia reperfusion-induced neuroinflammation and oxidative stress via PI3K/Akt/Nrf2 Activation. Oxid Med Cell Longev. 2018:86782672018. View Article : Google Scholar : PubMed/NCBI
39	Wu H, Ye M, Yang J and Ding J: Modulating endoplasmic reticulum stress to alleviate myocardial ischemia and reperfusion injury from basic research to clinical practice: A long way to go. Int J Cardiol. 223:630–631. 2016. View Article : Google Scholar : PubMed/NCBI
40	Tsai YG, Wen YS, Wang JY, Yang KD, Sun HL, Liou JH and Lin CY: Complement regulatory protein CD46 induces autophagy against oxidative stress-mediated apoptosis in normal and asthmatic airway epithelium. Sci Rep. 8:129732018. View Article : Google Scholar : PubMed/NCBI
41	Zhou M, Xu W, Wang J, Yan J, Shi Y, Zhang C, Ge W, Wu J, Du P and Chen Y: Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine. 35:345–360. 2018. View Article : Google Scholar : PubMed/NCBI
42	Zeng Z, Zhang YY, Tao S, et al: Protective effects of rapamycin on intestinal injury after intestinal ischemia-reperfusion in mouse. Med J Wuhan Univ. 40:192–196. 2019.
43	Jin S, Wei J, You L, Liu H and Qian W: Autophagy regulation and its dual role in blood cancers: A novel target for therapeutic development (Review). Oncol Rep. 39:2473–2481. 2018.PubMed/NCBI
44	Klionsky DJ and Emr SD: Autophagy as a regulated pathway of cellular degradation. Science. 290:1717–1721. 2000. View Article : Google Scholar : PubMed/NCBI
45	Pickrell AM and Youle RJ: The Roles of PINK1, Parkin, and mitochondrial fidelity in Parkinson's disease. Neuron. 85:257–273. 2015. View Article : Google Scholar : PubMed/NCBI
46	Durcan TM and Fon EA: The three ‘P's of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev. 29:989–999. 2015. View Article : Google Scholar : PubMed/NCBI
47	Arena G and Valente EM: PINK1 in the limelight: Multiple functions of an eclectic protein in human health and disease. J Pathol. 241:251–263. 2017. View Article : Google Scholar : PubMed/NCBI
48	Deas E, Piipari K, Machhada A, Li A, Gutierrez-del-Arroyo A, Withers DJ, Wood NW and Abramov AY: PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice. Open Biol. 4:1400512014. View Article : Google Scholar : PubMed/NCBI
49	Rosenberg CS: Wound healing in the patient with diabetes mellitus. Nurse Clin North Am. 25:247–253. 1990.
50	Scannel G, Waxman K, Vaziri ND, Zhang J, Kaupke CJ, Jalali M and Hecht CC: Hypoxia-induced alterations of neutrophil membrane receptors. J Surg Res. 59:141–145. 1995. View Article : Google Scholar : PubMed/NCBI
51	Thomaz Neto FJ, Koike MK, Abrahão Mde S, Carillo Neto F, Pereira RK, Machado JL and Montero EF: Ischemic preconditioning attenuates remote pulmonary inflammatory infiltration of diabetic rats with an intestinal and hepatic ischemia-reperfusion injury. Acta Cir Bras. 28:174–178. 2013. View Article : Google Scholar : PubMed/NCBI