Dual character of flavonoids in attenuating and aggravating ischemia‑reperfusion‑induced myocardial injury

Li,Wenqiang; Li,Yun; Sun,Ruifang; Zhou,Sumei; Li,Meifeng; Feng,Mingchen; Xie,Yingguang

doi:10.3892/etm.2017.4670

Dual character of flavonoids in attenuating and aggravating ischemia‑reperfusion‑induced myocardial injury

Authors:
- Wenqiang Li
- Yun Li
- Ruifang Sun
- Sumei Zhou
- Meifeng Li
- Mingchen Feng
- Yingguang Xie
View Affiliations

Affiliations: Department of Emergency, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China, Department of Joint Surgery, Jining First People's Hospital, Jining, Shandong 272011, P.R. China, Intensive Care Unit, Jining First People's Hospital, Jining, Shandong 272011, P.R. China, Intensive Care Unit, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, P.R. China
Published online on: June 26, 2017 https://doi.org/10.3892/etm.2017.4670
Pages: 1307-1314
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The concept that flavonoids exert cardioprotection against myocardial ischemia‑reperfusion (I/R) injury has been acknowledged by a large body of evidence. However, recent studies reported cardiotoxic effects of certain flavonoids, while the underlying mechanisms have remained largely elusive. Flavonoids have been demonstrated to activate aryl hydrocarbon receptor (Ahr), which is implicated in an array of cell signaling processes. The present study examined the cardioprotective roles of quercetin (Qu) and β‑naphthoflavone (β‑NF) against I/R injury and explored whether the underlying mechanism proceeds via molecular signaling downstream of Ahr. An oxygen glucose deprivation/reoxygenation (OGD/R) model of I/R was established in myocardial H9c2 cells in the absence or presence of Qu or β‑NF. Qu as well as β‑NF reversed OGD/R‑induced overproduction of reactive oxygen species by increasing the anti‑oxidative capacity of the cells and protected them from lethal injury, as demonstrated by a decreased cell death rate, lactate hydrogenase leakage and caspase‑3 activity as determined by flow cytometry, colorimetric assay and western blot analysis, respectively. Immunocytochemistry, co‑immunoprecipitation and western blot assays collectively revealed that Qu and β‑NF engendered the translocation of Ahr from the cytoplasm into the cell nucleus, where binding of Ahr with the Ahr nuclear translocator (ARNT) blocked its binding to hypoxia‑inducible factor (HIF)‑1α, which inhibited the cardioprotection of HIF‑1α, including the induction of nitric oxide (NO) and inhibition of vascular endothelial growth factor (VEGF) production. Ahr knockdown recovered the binding of ARNT to HIF‑1α and the generation of NO and VEGF. The results of the present study suggested a dual character of Qu and β‑NF in the process of myocardial I/R.

View Figures

View References

1	Wu WY, Wang WY, Ma YL, Yan H, Wang XB, Qin YL, Su M, Chen T and Wang YP: Sodium tanshinone IIA silate inhibits oxygen-glucose deprivation/recovery-induced cardiomyocyte apoptosis via suppression of the NF-κB/TNF-α pathway. Br J Pharmacol. 169:1058–1071. 2013. View Article : Google Scholar : PubMed/NCBI
2	Zhao D, Li Q, Huang Q, Li X, Yin M, Wang Z and Hong J: Cardioprotective effect of propofol against oxygen glucose deprivation and reperfusion injury in H9c2 cells. Oxid Med Cell Longev. 2015:1849382015. View Article : Google Scholar : PubMed/NCBI
3	Zhou T, Chuang CC and Zuo L: Molecular characterization of reactive oxygen species in myocardial ischemia-reperfusion injury. Biomed Res Int. 2015:8649462015. View Article : Google Scholar : PubMed/NCBI
4	Chen JY, Hu RY and Chou HC: Quercetin-induced cardioprotection against doxorubicin cytotoxicity. J Biomed Sci. 20:952013. View Article : Google Scholar : PubMed/NCBI
5	Wang Y, Zhang ZZ, Wu Y, Ke JJ, He XH and Wang YL: Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway. Braz J Med Biol Res. 46:861–867. 2013. View Article : Google Scholar : PubMed/NCBI
6	Dong Q, Chen L, Lu Q, Sharma S, Li L, Morimoto S and Wang G: Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression. Br J Pharmacol. 171:4440–4454. 2014. View Article : Google Scholar : PubMed/NCBI
7	Ozbek N, Bali EB and Karasu C: Quercetin and hydroxytyrosol attenuates xanthine/xanthine oxidase-induced toxicity in H9c2 cardiomyocytes by regulation of oxidative stress and stress-sensitive signaling pathways. Gen Physiol Biophys. 34:407–414. 2015.PubMed/NCBI
8	Agrawal YO, Sharma PK, Shrivastava B, Ojha S, Upadhya HM, Arya DS and Goyal SN: Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats. PLoS One. 9:e1112122014. View Article : Google Scholar : PubMed/NCBI
9	Nannelli A, Rossignolo F, Tolando R, Rossato P, Longo V and Gervasi PG: Effect of beta-naphthoflavone on AhR-regulated genes (CYP1A1, 1A2, 1B1, 2S1, Nrf2, and GST) and antioxidant enzymes in various brain regions of pig. Toxicology. 265:69–79. 2009. View Article : Google Scholar : PubMed/NCBI
10	Morrissy S, Strom J, Purdom-Dickinson S and Chen QM: NAD (P)H:quinone oxidoreductase 1 is induced by progesterone in cardiomyocytes. Cardiovasc Toxicol. 12:108–114. 2012. View Article : Google Scholar : PubMed/NCBI
11	Higgins LG and Hayes JD: Mechanisms of induction of cytosolic and microsomal glutathione transferase (GST) genes by xenobiotics and pro-inflammatory agents. Drug Metab Rev. 43:92–137. 2011. View Article : Google Scholar : PubMed/NCBI
12	Reed JR, Cawley GF and Backes WL: Inhibition of cytochrome P450 1A2-mediated metabolism and production of reactive oxygen species by heme oxygenase-1 in rat liver microsomes. Drug Metab Lett. 5:6–16. 2011. View Article : Google Scholar : PubMed/NCBI
13	Daubney J, Bonner PL, Hargreaves AJ and Dickenson JM: Cardioprotective and cardiotoxic effects of quercetin and two of its in vivo metabolites on differentiated h9c2 cardiomyocytes. Basic Clin Pharmacol Toxicol. 116:96–109. 2015. View Article : Google Scholar : PubMed/NCBI
14	Zordoky BN and El-Kadi AO: 2,3,7,8-Tetrachlorodibenzo-p-dioxin and beta-naphthoflavone induce cellular hypertrophy in H9c2 cells by an aryl hydrocarbon receptor-dependant mechanism. Toxicol In Vitro. 24:863–871. 2010. View Article : Google Scholar : PubMed/NCBI
15	Vrba J, Kren V, Vacek J, Papouskova B and Ulrichova J: Quercetin, quercetin glycosides and taxifolin differ in their ability to induce AhR activation and CYP1A1 expression in HepG2 cells. Phytother Res. 26:1746–1752. 2012. View Article : Google Scholar : PubMed/NCBI
16	Smith KJ, Murray IA, Tanos R, Tellew J, Boitano AE, Bisson WH, Kolluri SK, Cooke MP and Perdew GH: Identification of a high-affinity ligand that exhibits complete aryl hydrocarbon receptor antagonism. J Pharmacol Exp Ther. 338:318–327. 2011. View Article : Google Scholar : PubMed/NCBI
17	Narayanan GA, Murray IA, Krishnegowda G, Amin S and Perdew GH: Selective aryl hydrocarbon receptor modulator-mediated repression of CD55 expression induced by cytokine exposure. J Pharmacol Exp Ther. 342:345–355. 2012. View Article : Google Scholar : PubMed/NCBI
18	Tsai CH, Li CH, Liao PL, Cheng YW, Lin CH, Huang SH and Kang JJ: NcoA2-dependent inhibition of HIF-1α activation is regulated via AhR. Toxicol Sci. 48:17–30. 2015.
19	Ong SG and Hausenloy DJ: Hypoxia-inducible factor as a therapeutic target for cardioprotection. Pharmacol Ther. 136:69–81. 2012. View Article : Google Scholar : PubMed/NCBI
20	Adluri RS, Thirunavukkarasu M, Dunna NR, Zhan L, Oriowo B, Takeda K, Sanchez JA, Otani H, Maulik G, Fong GH and Maulik N: Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1α transcription factor and its target genes in mice. Antioxid Redox Signal. 15:1789–1797. 2011. View Article : Google Scholar : PubMed/NCBI
21	Bandarra D, Biddlestone J, Mudie S, Müller HA and Rocha S: HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals. Dis Model Mech. 8:169–181. 2015. View Article : Google Scholar : PubMed/NCBI
22	Poynter JA, Manukyan MC, Wang Y, Brewster BD, Herrmann JL, Weil BR, Abarbanell AM and Meldrum DR: Systemic pretreatment with dimethyloxalylglycine increases myocardial HIF-1α and VEGF production and improves functional recovery after acute ischemia/reperfusion. Surgery. 150:278–283. 2011. View Article : Google Scholar : PubMed/NCBI
23	Siu KL, Lotz C, Ping P and Cai H: Netrin-1 abrogates ischemia/reperfusion-induced cardiac mitochondrial dysfunction via nitric oxide-dependent attenuation of NOX4 activation and recoupling of NOS. J Mol Cell Cardiol. 78:174–185. 2015. View Article : Google Scholar : PubMed/NCBI
24	Alánová P, Kolář F, Ošťádal B and Neckář J: Role of NO/cGMP signaling pathway in cardiac ischemic tolerance of chronically hypoxic rats. Physiol Res. 64:783–787. 2015.PubMed/NCBI
25	Totzeck M, Hendgen-Cotta U and Rassaf T: Concepts of hypoxic NO signaling in remote ischemic preconditioning. World J Cardiol. 7:645–651. 2015. View Article : Google Scholar : PubMed/NCBI
26	Bir SC, Pattillo CB, Pardue S, Kolluru GK, Shen X, Giordano T and Kevil CG: Nitrite anion therapy protects against chronic ischemic tissue injury in db/db diabetic mice in a NO/VEGF-dependent manner. Diabetes. 63:270–281. 2014. View Article : Google Scholar : PubMed/NCBI