Troxerutin attenuates oxygen‑glucose deprivation and reoxygenation‑induced oxidative stress and inflammation by enhancing the PI3K/AKT/HIF‑1α signaling pathway in H9C2 cardiomyocytes

Yu,Zhang‑Ping; Yu,Han‑Qiao; Li,Jun; Li,Chao; Hua,Xian; Sheng,Xiao‑Sheng

doi:10.3892/mmr.2020.11207

Troxerutin attenuates oxygen‑glucose deprivation and reoxygenation‑induced oxidative stress and inflammation by enhancing the PI3K/AKT/HIF‑1α signaling pathway in H9C2 cardiomyocytes

Authors:
- Zhang‑Ping Yu
- Han‑Qiao Yu
- Jun Li
- Chao Li
- Xian Hua
- Xiao‑Sheng Sheng
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Affiliations: Department of Cardiology, Jinhua People's Hospital, Jinhua, Zhejiang 321000, P.R. China
Published online on: June 3, 2020 https://doi.org/10.3892/mmr.2020.11207
Pages: 1351-1361
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Myocardial ischemia‑reperfusion (MI/R) injury is a complex pathological process that occurs when tissues are reperfused following a prolonged period of ischemia. Troxerutin has been reported to have cardioprotective functions. However, the underlying mechanism by which troxerutin protects against MI/R injury has not been fully elucidated. The aim of the present study was to explore whether troxerutin‑mediated protection against oxygen‑glucose deprivation/reoxygenation (OGD/R)‑induced H9C2 cell injury was associated with the inhibition of oxidative stress and the inflammatory response by regulating the PI3K/AKT/hypoxia‑inducible factor‑1α (HIF‑1α) signaling pathway. The results of the present study suggested that troxerutin pretreatment prevented the OGD/R‑induced reduction in cell viability, and the increase in lactate dehydrogenase activity and apoptosis. Troxerutin reversed OGD/R‑induced the inhibition of the PI3K/AKT/HIF‑1α signaling pathway as demonstrated by the increased expression of PI3K and HIF‑1α, and the increased ratio of phosphorylated AKT/AKT. LY294002, a selective PI3K inhibitor, inhibited the PI3K/AKT/HIF‑1α signaling pathway and further attenuated the protective effect of troxerutin against OGD/R‑induced H9C2 cell damage. Furthermore, small interfering (si)RNA‑mediated knockdown of HIF‑1α reduced troxerutin‑induced protection against OGD/R injury. Troxerutin pretreatment alleviated OGD/R‑induced oxidative stress, as demonstrated by the reduced generation of reactive oxygen species and malonaldehyde content, and the increased activities of superoxide dismutase and glutathione peroxidase, which were reduced by HIF‑1α‑siRNA. Troxerutin‑induced decreases in the levels of interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α in OGD/R conditions were also reduced by HIF‑1α‑siRNA. The results from the present study indicated that troxerutin aggravated OGD/R‑induced H9C2 cell injury by inhibiting oxidative stress and the inflammatory response. The primary underlying protective mechanism of troxerutin was mediated by the activation of the PI3K/AKT/HIF‑1α signaling pathway.

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1	Kalogeris T, Baines CP, Krenz M and Korthuis RJ: Ischemia/reperfusion. Compr Physiol. 7:113–170. 2016. View Article : Google Scholar : PubMed/NCBI
2	Yang CF: Clinical manifestations and basic mechanisms of myocardial ischemia/reperfusion injury. Ci Ji Yi Xue Za Zhi. 30:209–215. 2018.PubMed/NCBI
3	Hausenloy DJ and Yellon DM: Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J Clin Invest. 123:92–100. 2013. View Article : Google Scholar : PubMed/NCBI
4	Donato M, Evelson P and Gelpi RJ: Protecting the heart from ischemia/reperfusion injury: An update on remote ischemic preconditioning and postconditioning. Curr Opin Cardiol. 32:784–790. 2017. View Article : Google Scholar : PubMed/NCBI
5	Hentia C, Rizzato A, Camporesi E, Yang Z, Muntean DM, Săndesc D and Bosco G: An overview of protective strategies against ischemia/reperfusion injury: The role of hyperbaric oxygen preconditioning. Brain Behav. 8:e009592018. View Article : Google Scholar : PubMed/NCBI
6	Huang Z, Zhang L, Wang Y, Gao H, Li X, Huang X and Huang T: Effects of rutin and its derivatives on citrinin production by Monascus aurantiacus Li AS3.4384 in liquid fermentation using different types of media. Food Chem. 284:205–212. 2019. View Article : Google Scholar : PubMed/NCBI
7	Zavvari Oskuye Z, Mirzaei Bavil F, Hamidian GR, Mehri K, Qadiri A, Ahmadi M, Oghbaei H, Vatankhah AM and Keyhanmanesh R: Troxerutin affects the male fertility in prepubertal type 1 diabetic male rats. Iran J Basic Med Sci. 22:197–205. 2019.PubMed/NCBI
8	Raja B, Saranya D and Prabhu R: Role of flavonoid troxerutin on blood pressure, oxidative stress and regulation of lipid metabolism. Front Biosci (Elite Ed). 11:121–129. 2019. View Article : Google Scholar : PubMed/NCBI
9	Xin X, Zhang M, Li X, Lai F and Zhao G: Biocatalytic synthesis of acylated derivatives of troxerutin: Their bioavailability and antioxidant properties in vitro. Microb Cell Fact. 17:1302018. View Article : Google Scholar : PubMed/NCBI
10	Najafi M, Noroozi E, Javadi A and Badalzadeh R: Anti-arrhythmogenic and anti-inflammatory effects of troxerutin in ischemia/reperfusion injury of diabetic myocardium. Biomed Pharmacother. 102:385–391. 2018. View Article : Google Scholar : PubMed/NCBI
11	Yu Y and Zheng G: Troxerutin protects against diabetic cardiomyopathy through NFkappaB/AKT/IRS1 in a rat model of type 2 diabetes. Mol Med Rep. 15:3473–3478. 2017. View Article : Google Scholar : PubMed/NCBI
12	Mokhtari B, Badalzadeh R, Alihemmati A and Mohammadi M: Phosphorylation of GSK-3β and reduction of apoptosis as targets of troxerutin effect on reperfusion injury of diabetic myocardium. Eur J Pharmacol. 765:316–321. 2015. View Article : Google Scholar : PubMed/NCBI
13	Badalzadeh R, Baradaran B, Alihemmati A, Yousefi B and Abbaszadeh A: Troxerutin preconditioning and ischemic postconditioning modulate inflammatory response after myocardial ischemia/reperfusion injury in rat model. Inflammation. 40:136–143. 2017. View Article : Google Scholar : PubMed/NCBI
14	Gielis JF, Beckers PAJ, Briede JJ, Cos P and Van Schil PE: Oxidative and nitrosative stress during pulmonary ischemia-reperfusion injury: From the lab to the OR. Ann Transl Med. 5:1312017. View Article : Google Scholar : PubMed/NCBI
15	Hernandez-Resendiz S, Chinda K, Ong SB, Cabrera-Fuentes H, Zazueta C and Hausenloy DJ: The role of redox dysregulation in the inflammatory response to Acute myocardial ischaemia-reperfusion injury-adding fuel to the fire. Curr Med Chem. 25:1275–1293. 2018. View Article : Google Scholar : PubMed/NCBI
16	Cadenas S: ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med. 117:76–89. 2018. View Article : Google Scholar : PubMed/NCBI
17	Gonzalez-Montero J, Brito R, Gajardo AI and Rodrigo R: Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities. World J Cardiol. 10:74–86. 2018. View Article : Google Scholar : PubMed/NCBI
18	Katsuki S, Matoba T, Koga JI, Nakano K and Egashira K: Anti-inflammatory nanomedicine for cardiovascular disease. Front Cardiovasc Med. 4:872017. View Article : Google Scholar : PubMed/NCBI
19	Sinning C, Westermann D and Clemmensen P: Oxidative stress in ischemia and reperfusion: Current concepts, novel ideas and future perspectives. Biomark Med. 11:11031–11040. 2017. View Article : Google Scholar : PubMed/NCBI
20	Sun XH, Wang X, Zhang Y and Hui J: Exosomes of bone-marrow stromal cells inhibit cardiomyocyte apoptosis under ischemic and hypoxic conditions via miR-486-5p targeting the PTEN/PI3K/AKT signaling pathway. Thromb Res. 177:23–32. 2019. View Article : Google Scholar : PubMed/NCBI
21	Yao H and Han X and Han X: The cardioprotection of the insulin-mediated PI3K/Akt/mTOR signaling pathway. Am J Cardiovasc Drugs. 14:433–442. 2014. View Article : Google Scholar : PubMed/NCBI
22	Agani F and Jiang BH: Oxygen-independent regulation of HIF-1: Novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets. 13:245–251. 2013. View Article : Google Scholar : PubMed/NCBI
23	Brocato J, Chervona Y and Costa M: Molecular responses to hypoxia-inducible factor 1α and beyond. Mol Pharmacol. 85:651–657. 2014. View Article : Google Scholar : PubMed/NCBI
24	Jianqiang P, Ping Z, Xinmin F, Zhenhua Y, Ming Z and Ying G: Expression of hypoxia-inducible factor 1 alpha ameliorate myocardial ischemia in rat. Biochem Biophys Res Commun. 465:691–695. 2015. View Article : Google Scholar : PubMed/NCBI
25	Li M, Cui Y, He W, Deng X, Wang Y, Cai M, Wang Y, Pei J, Mei X and Wu P: Effects of triple-mutated hypoxia-inducible factor-1α on angiogenesis and cardiac function improvement in rats with myocardial infarction. Cell Physiol Biochem. 50:2329–2340. 2018. View Article : Google Scholar : PubMed/NCBI
26	Man S, Chai H, Cui J, Yao J, Ma L and Gao W: Antitumor and anti-metastatic mechanisms of Rhizoma paridis saponins in Lewis mice. Environ Toxicol. 33:149–155. 2018. View Article : Google Scholar : PubMed/NCBI
27	Movafagh S, Crook S and Vo K: Regulation of hypoxia-inducible factor-1a by reactive oxygen species: New developments in an old debate. J Cell Biochem. 116:696–703. 2015. View Article : Google Scholar : PubMed/NCBI
28	Liang S, Wang Y and Liu Y: Dexmedetomidine alleviates lung ischemia-reperfusion injury in rats by activating PI3K/Akt pathway. Eur Rev Med Pharmacol Sci. 23:370–377. 2019.PubMed/NCBI
29	Liang Z, Chi YJ, Lin GQ, Luo SH, Jiang QY and Chen YK: MiRNA-26a promotes angiogenesis in a rat model of cerebral infarction via PI3K/AKT and MAPK/ERK pathway. Eur Rev Med Pharmacol Sci. 22:3485–3492. 2018.PubMed/NCBI
30	Wei J and Wu J, Xu W, Nie H, Zhou R, Wang R, Liu Y, Tang G and Wu J: Salvianolic acid B inhibits glycolysis in oral squamous cell carcinoma via targeting PI3K/AKT/HIF-1α signaling pathway. Cell Death Dis. 9:5992018. View Article : Google Scholar : PubMed/NCBI
31	Shu L, Zhang W, Huang G, Huang C, Zhu X, Su G and Xu J: Troxerutin attenuates myocardial cell apoptosis following myocardial ischemia-reperfusion injury through inhibition of miR-146a-5p expression. J Cell Physiol. 234:9274–9282. 2019. View Article : Google Scholar : PubMed/NCBI
32	Liu J, Sui H, Zhao J and Wang Y: Osmotin protects H9c2 cells from simulated ischemia-reperfusion injury through AdipoR1/PI3K/AKT signaling pathway. Front Physiol. 8:6112017. View Article : Google Scholar : PubMed/NCBI
33	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
34	Liu Q, Li J, Wang J, Li J, Janicki JS and Fan D: Effects and mechanisms of chinese herbal medicine in ameliorating myocardial ischemia-reperfusion injury. Evid Based Complement Alternat Med. 2013:9256252013. View Article : Google Scholar : PubMed/NCBI
35	Shu L, Zhang W, Huang C, Huang G and Su G: Troxerutin protects against myocardial ischemia/reperfusion injury Via Pi3k/Akt pathway in rats. Cell Physiol Biochem. 44:1939–1948. 2017. View Article : Google Scholar : PubMed/NCBI
36	Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW and Thistlethwaite PA: Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med. 342:626–633. 2000. View Article : Google Scholar : PubMed/NCBI
37	Semenza GL: HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985). 88:1474–1480. 2000. View Article : Google Scholar : PubMed/NCBI
38	Sun N, Meng F, Xue N, Pang G, Wang Q and Ma H: Inducible miR-145 expression by HIF-1a protects cardiomyocytes against apoptosis via regulating SGK1 in simulated myocardial infarction hypoxic microenvironment. Cardiol J. 25:268–278. 2018.PubMed/NCBI
39	Yu L, Zhang W, Huang C, Liang Q, Bao H, Gong Z, Xu M, Wang Z, Wen M and Cheng X: FoxO4 promotes myocardial ischemia-reperfusion injury: The role of oxidative stress-induced apoptosis. Am J Transl Res. 10:2890–2900. 2018.PubMed/NCBI
40	Ma W, Wang S, Liu X, Tang F, Zhao P, Cheng K, Zheng Q, Zhuo Y, Zhao X, Li X and Feng W: Protective effect of troxerutin and cerebroprotein hydrolysate injection on cerebral ischemia through inhibition of oxidative stress and promotion of angiogenesis in rats. Mol Med Rep. 19:3148–3158. 2019.PubMed/NCBI
41	Geetha R, Sathiya Priya C and Anuradha CV: Troxerutin abrogates mitochondrial oxidative stress and myocardial apoptosis in mice fed calorie-rich diet. Chem Biol Interact. 278:74–83. 2017. View Article : Google Scholar : PubMed/NCBI
42	Sies H: Oxidative stress: A concept in redox biology and medicine. Redox Biol. 4:180–183. 2015. View Article : Google Scholar : PubMed/NCBI
43	Czerska M, Mikołajewska K, Zieliński M, Gromadzińska J and Wąsowicz W: Today's oxidative stress markers. Med Pr. 66:393–405. 2015. View Article : Google Scholar : PubMed/NCBI
44	Ong SB, Hernández-Reséndiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek XY, Cabrera-Fuentes HA and Hausenloy DJ: Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther. 186:73–87. 2018. View Article : Google Scholar : PubMed/NCBI
45	Zhào H, Liu Y, Zeng J, Li D, Zhang W and Huang Y: Troxerutin and cerebroprotein hydrolysate injection protects neurovascular units from oxygen-glucose deprivation and reoxygenation-induced injury in vitro. Evid Based Complement Alternat Med. 2018:98596722018. View Article : Google Scholar : PubMed/NCBI
46	Shan Q, Zheng GH, Han XR, Wen X, Wang S, Li MQ, Zhuang J, Zhang ZF, Hu B, Zhang Y and Zheng YL: Troxerutin protects kidney tissue against BDE-47-induced inflammatory damage through CXCR4-TXNIP/NLRP3 signaling. Oxid Med Cell Longev. 2018:98654952018. View Article : Google Scholar : PubMed/NCBI
47	Shan Q, Zhuang J, Zheng G, Zhang Z, Zhang Y, Lu J and Zheng Y: Troxerutin reduces kidney damage against BDE-47-induced apoptosis via inhibiting NOX2 activity and increasing Nrf2 activity. Oxid Med Cell Longev. 2017.6034692. View Article : Google Scholar
48	Qiu Z, Lei S, Zhao B, Wu Y, Su W, Liu M, Meng Q, Zhou B, Leng Y and Xia ZY: NLRP3 inflammasome activation-mediated pyroptosis aggravates myocardial ischemia/reperfusion injury in diabetic rats. Oxid Med Cell Longev. 2017:97432802017. View Article : Google Scholar : PubMed/NCBI
49	Shen Y, Liu X, Shi J and Wu X: Involvement of Nrf2 in myocardial ischemia and reperfusion injury. Int J Biol Macromol. 125:496–502. 2019. View Article : Google Scholar : PubMed/NCBI