Hydrogen sulfide protects H9c2 cardiac cells against doxorubicin-induced cytotoxicity through the PI3K/Akt/FoxO3a pathway

Liu,Mi-Hua; Zhang,Yuan; He,Jun; Tan,Tian-Ping; Wu,Shao-Jian; Guo,Dong-Ming; He,Hui; Peng,Juan; Tang,Zhi-Han; Jiang,Zhi-Sheng

doi:10.3892/ijmm.2016.2563

Hydrogen sulfide protects H9c2 cardiac cells against doxorubicin-induced cytotoxicity through the PI3K/Akt/FoxO3a pathway

Authors:
- Mi-Hua Liu
- Yuan Zhang
- Jun He
- Tian-Ping Tan
- Shao-Jian Wu
- Dong-Ming Guo
- Hui He
- Juan Peng
- Zhi-Han Tang
- Zhi-Sheng Jiang
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Affiliations: Department of Clinical Laboratory, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China, Department of Pathology, Mawangdui Hospital, Changsha, Hunan 410016, P.R. China, Laboratory of Clinical Anatomy, University of South China, Hengyang, Hunan 421001, P.R. China, Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: April 14, 2016 https://doi.org/10.3892/ijmm.2016.2563
Pages: 1661-1668

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Abstract

Doxorubicin (DOX) is an efficient drug used in cancer therapy that also produces reactive oxygen species (ROS) that induces severe cytotoxicity, which limits its clinical application. Hydrogen sulfide (H2S), a novel gasotransmitter, has been shown to exert cardioprotective effects. The present study aimed to determine whether exogenous H2S protects H9c2 cardiac cells against DOX-induced cytotoxicity and whether these protective effects are mediated through the PI3K/Akt/FoxO3a pathway. The H9c2 cardiac cells were exposed to 5 µM DOX for 24 h to establish a model of DOX-induced cardiotoxicity. The results showed that the treatment of H9c2 cardiac cells with sodium hydrosulﬁde (NaHS) for 30 min prior to DOX exposure markedly attenuated the phosphorylation of Akt and FoxO3a. Notably, pre-treatment of the H9c2 cells with NaHS significantly attenuated the nuclear localization of FoxO3a as well as the apoptosis of H9c2 cells induced by DOX. The treatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of ROS, prior to DOX exposure, also markedly increased the phosphorylation of Akt and FoxO3a which was inhibited by DOX alone. Furthermore, pre-treatment with LY294002, a selective inhibitor of PI3K/Akt, reversed the protective effect of H2S against DOX-induced injury of cardiomyocytes, as demonstrated by an increased number of apoptotic cells, a decrease in cell viability and the reduced phosphorylation of Akt and FoxO3a. These ﬁndings suggested that exogenous H2S attenuates DOX-induced cytotoxic effects in H9c2 cardiac cells through the PI3K/Akt/FoxO3a pathway.

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1	Magnano LC, Martínez Cibrian N, Andrade González X and Bosch X: Cardiac complications of chemotherapy: role of prevention. Curr Treat Options Cardiovasc Med. 16:3122014. View Article : Google Scholar : PubMed/NCBI
2	Truong J, Yan AT, Cramarossa G and Chan KK: Chemotherapy-induced cardiotoxicity: detection, prevention, and management. Can J Cardiol. 30:869–878. 2014. View Article : Google Scholar : PubMed/NCBI
3	Spagnuolo RD, Recalcati S, Tacchini L and Cairo G: Role of hypoxia-inducible factors in the dexrazoxane-mediated protection of cardiomyocytes from doxorubicin-induced toxicity. Br J Pharmacol. 163:299–312. 2011. View Article : Google Scholar : PubMed/NCBI
4	Zhang Y, Tang ZH, Ren Z, Qu SL, Liu MH, Liu LS and Jiang ZS: Hydrogen sulfide, the next potent preventive and therapeutic agent in aging and age-associated diseases. Mol Cell Biol. 33:1104–1113. 2013. View Article : Google Scholar : PubMed/NCBI
5	Osipov RM, Robich MP, Feng J, Liu Y, Clements RT, Glazer HP, Sodha NR, Szabo C, Bianchi C and Sellke FW: Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion: comparison of different administration regimens and characterization of the cellular mechanisms of protection. J Cardiovasc Pharmacol. 54:287–297. 2009. View Article : Google Scholar : PubMed/NCBI
6	Huang YE, Tang ZH, Xie W, Shen XT, Liu MH, Peng XP, Zhao ZZ, Nie DB, Liu LS and Jiang ZS: Endogenous hydrogen sulfide mediates the cardioprotection induced by ischemic post-conditioning in the early reperfusion phase. Exp Ther Med. 4:1117–1123. 2012.PubMed/NCBI
7	Wang H, Zhou X, Huang J, Mu N, Guo Z, Wen Q, Wang R, Chen S, Feng ZP and Zheng W: The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells. Psychopharmacology (Berl). 228:129–141. 2013. View Article : Google Scholar
8	van der Vos KE and Coffer PJ: The extending network of FOXO transcriptional target genes. Antioxid Redox Signal. 14:579–592. 2011. View Article : Google Scholar
9	Sanphui P and Biswas SC: FoxO3a is activated and executes neuron death via Bim in response to β-amyloid. Cell Death Dis. 4:e6252013. View Article : Google Scholar
10	Bao W, Pan F, Chen L, Su G, Gao X, Li Y, Sun Q, Sun J, He K and Song H: The PI3K/AKT pathway and FOXO3a transcription factor mediate high glucose-induced apoptosis in neonatal rat ventricular myocytes. Iran Red Crescent Med J. 16:e149142014. View Article : Google Scholar : PubMed/NCBI
11	Li D, Qu Y, Mao M, Zhang X, Li J, Ferriero D and Mu D: Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia. J Cereb Blood Flow Metab. 29:1903–1913. 2009. View Article : Google Scholar : PubMed/NCBI
12	Liu MH, Yuan C, He J, Tan TP, Wu SJ, Fu HY, Liu J, Yu S, Chen YD, Le QF, et al: Resveratrol protects PC12 cells from high glucose-induced neurotoxicity via PI3K/Akt/FoxO3a pathway. Cell Mol Neurobiol. 35:513–522. 2014. View Article : Google Scholar : PubMed/NCBI
13	Zhang MQ, Zheng YL, Chen H, Tu JF, Shen Y, Guo JP, Yang XH, Yuan SR, Chen LZ, Chai JJ, et al: Sodium tanshinone IIA sulfonate protects rat myocardium against ischemia-reperfusion injury via activation of PI3K/Akt/FOXO3A/Bim pathway. Acta Pharmacol Sin. 34:1386–1396. 2013. View Article : Google Scholar : PubMed/NCBI
14	Juhasz B, Thirunavukkarasu M, Pant R, Zhan L, Penumathsa SV, Secor ER Jr, Srivastava S, Raychaudhuri U, Menon VP, Otani H, et al: Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium. Am J Physiol Heart Circ Physiol. 294:H1365–H1370. 2008. View Article : Google Scholar : PubMed/NCBI
15	Guo R, Wu K, Chen J, Mo L, Hua X, Zheng D, Chen P, Chen G, Xu W and Feng J: Exogenous hydrogen sulfide protects against doxorubicin-induced inflammation and cytotoxicity by inhibiting p38MAPK/NFκB pathway in H9c2 cardiac cells. Cell Physiol Biochem. 32:1668–1680. 2013.
16	Tocchetti CG, Carpi A, Coppola C, Quintavalle C, Rea D, Campesan M, Arcari A, Piscopo G, Cipresso C, Monti MG, et al: Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction. Eur J Heart Fail. 16:358–366. 2014. View Article : Google Scholar : PubMed/NCBI
17	Wang XY, Yang CT, Zheng DD, Mo LQ, Lan AP, Yang ZL, Hu F, Chen PX, Liao XX and Feng JQ: Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress. Mol Cell Biochem. 363:419–426. 2012. View Article : Google Scholar
18	Su YW, Liang C, Jin HF, Tang XY, Han W, Chai LJ, Zhang CY, Geng B, Tang CS and Du JB: Hydrogen sulfide regulates cardiac function and structure in adriamycin-induced cardiomyopathy. Circ J. 73:741–749. 2009. View Article : Google Scholar : PubMed/NCBI
19	Kim KH, Oudit GY and Backx PH: Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. J Pharmacol Exp Ther. 324:160–169. 2008. View Article : Google Scholar
20	An T, Zhang Y, Huang Y, Zhang R, Yin S, Guo X, Wang Y, Zou C, Wei B, Lv R, et al: Neuregulin-1 protects against doxorubicin-induced apoptosis in cardiomyocytes through an Akt-dependent pathway. Physiol Res. 62:379–385. 2013.PubMed/NCBI
21	Hong HJ, Liu JC, Chen PY, Chen JJ, Chan P and Cheng TH: Tanshinone IIA prevents doxorubicin-induced cardiomyocyte apoptosis through Akt-dependent pathway. Int J Cardiol. 157:174–179. 2012. View Article : Google Scholar
22	Chen YL, Loh SH, Chen JJ and Tsai CS: Urotensin II prevents cardiomyocyte apoptosis induced by doxorubicin via Akt and ERK. Eur J Pharmacol. 680:88–94. 2012. View Article : Google Scholar : PubMed/NCBI
23	Ho KK, McGuire VA, Koo CY, Muir KW, de Olano N, Maifoshie E, Kelly DJ, McGovern UB, Monteiro LJ, Gomes AR, et al: Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin. J Biol Chem. 287:1545–1555. 2012. View Article : Google Scholar :
24	Wang Y, Zhou Y and Graves DT: FOXO transcription factors: their clinical significance and regulation. Biomed Res Int. 2014:9253502014.PubMed/NCBI
25	Storz P: Forkhead homeobox type O transcription factors in the responses to oxidative stress. Antioxid Redox Signal. 14:593–605. 2011. View Article : Google Scholar :
26	Peng C, Ma J, Gao X, Tian P, Li W and Zhang L: High glucose induced oxidative stress and apoptosis in cardiac microvascular endothelial cells are regulated by FoxO3a. PLoS One. 8:e797392013. View Article : Google Scholar : PubMed/NCBI
27	Zhang S, Zhao Y, Xu M, Yu L, Zhao Y, Chen J, Yuan Y, Zheng Q and Niu X: FoxO3a modulates hypoxia stress induced oxidative stress and apoptosis in cardiac microvascular endothelial cells. PLoS One. 8:e803422013. View Article : Google Scholar : PubMed/NCBI
28	Pan Q, Xie X, Guo Y and Wang H: Simvastatin promotes cardiac microvascular endothelial cells proliferation, migration and survival by phosphorylation of p70 S6K and FoxO3a. Cell Biol Int. 38:599–609. 2014. View Article : Google Scholar : PubMed/NCBI
29	Jia Y, Mo SJ, Feng QQ, Zhan ML, OuYang LS, Chen JC, Ma YX, Wu JJ and Lei WL: EPO-dependent activation of PI3K/Akt/FoxO3a signalling mediates neuroprotection in in vitro and in vivo models of Parkinson's disease. J Mol Neurosci. 53:117–124. 2014. View Article : Google Scholar : PubMed/NCBI