Salidroside protects against hydrogen peroxide-induced injury in HUVECs via the regulation of REDD1 and mTOR activation

Xu,Mao-Chun; Shi,Hai-Ming; Wang,Hao; Gao,Xiu-Fang

doi:10.3892/mmr.2013.1468

Salidroside protects against hydrogen peroxide-induced injury in HUVECs via the regulation of REDD1 and mTOR activation

Authors:
- Mao-Chun Xu
- Hai-Ming Shi
- Hao Wang
- Xiu-Fang Gao
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Affiliations: Department of Cardiology, Huashan Hospital of Fudan University, Shanghai 200040, P.R. China, The Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai Medical School of Fudan University, Shanghai 200032, P.R. China
Published online on: May 9, 2013 https://doi.org/10.3892/mmr.2013.1468
Pages: 147-153

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Abstract

Antioxidative therapy is considered an effective strategy for treating oxidative stress-induced apoptosis in cardiovascular diseases. Salidroside has been used as an antioxidative therapy for oxidative injury in cardiac diseases. However, the mechanism underlying its antioxidant effect is poorly understood. The present study aimed to investigate the pharmacological effects of salidroside on cultured human umbilical vein endothelial cells (HUVECs) under conditions of oxidative injury induced by hydrogen peroxide (H2O2) and the underlying mechanisms in vitro. HUVECs pretreated with or without salidroside for 24 h were exposed to H2O2-induced oxidative stress conditions for 6 h and then cell viability, apoptosis, HIF-1α, regulated in development and DNA damage responses-1 (REDD1) and the PI3K/Akt/mTOR pathway were investigated. The results demonstrated that salidroside effectively attenuated H2O2-impaired cell viability and the production of reactive oxygen species (ROS) in a concentration-dependent manner. Reduced H2O2-induced apoptosis and activation of the cellular PI3K/Akt/mTOR pathway were demonstrated in HUVECs pretreated with salidroside. Furthermore, the level of REDD1, a direct regulator of mitochondrial metabolism, significantly increased in parallel with the level of HIF-1α following pretreatment with salidroside. The antioxidative effect of salidroside was abrogated in REDD1 knockdown cells. However, LY294002, a PI3K inhibitor, attenuated the anti-apoptotic effect of salidroside and blocked the increase of Akt and mTOR; however, did not affect the antioxidative effect of salidroside. These findings suggested that salidroside was capable of protecting HUVECs against H2O2-induced apoptosis by activating the PI3K/Akt/mTOR-dependent pathway and inhibiting ROS production by activating REDD1.

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1	Hirooka Y, Sagara Y, Kishi T and Sunagawa K: Oxidative stress and central cardiovascular regulation. Pathogenesis of hypertension and therapeutic aspects. Circ J. 74:827–835. 2010. View Article : Google Scholar : PubMed/NCBI
2	Stocker R and Keaney JF Jr: Role of oxidative modifications in atherosclerosis. Physiol Rev. 84:1381–1478. 2004. View Article : Google Scholar : PubMed/NCBI
3	Suzuki YJ, Jain V, Park AM and Day RM: Oxidative stress and oxidant signaling in obstructive sleep apnea and associated cardiovascular diseases. Free Radic Biol and Med. 40:1683–1692. 2006. View Article : Google Scholar : PubMed/NCBI
4	Kumar D and Jugdutt BI: Apoptosis and oxidants in the heart. J Lab Clin Med. 142:288–297. 2003. View Article : Google Scholar : PubMed/NCBI
5	Zhu YZ, Huang SH, Tan BK, Sun J, Whiteman M and Zhu YC: Antioxidants in Chinese herbal medicines: a biochemical perspective. Nat Prod Rep. 21:478–489. 2004. View Article : Google Scholar : PubMed/NCBI
6	Fingar DC and Blenis J: Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 23:3151–3171. 2004. View Article : Google Scholar : PubMed/NCBI
7	Proud CG: The multifaceted role of mTOR in cellular stress responses. DNA Repair (Amst). 3:927–934. 2004. View Article : Google Scholar : PubMed/NCBI
8	Hornberger TA, Stuppard R, Conley KE, et al: Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide 3-kinase-, protein kinase B- and growth factor-independent mechanism. Biochem J. 380:795–804. 2004. View Article : Google Scholar
9	Reiling JH and Sabatini DM: Stress and mTORture signaling. Oncogene. 25:6373–6383. 2006. View Article : Google Scholar : PubMed/NCBI
10	Peterson TR, Laplante M, Thoreen CC, et al: DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 137:873–886. 2009. View Article : Google Scholar : PubMed/NCBI
11	Vander Haar E, Lee S, Bandhakavi S, Griffin TJ and Kim DH: Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 9:316–323. 2007.PubMed/NCBI
12	Sofer A, Lei K, Johannessen CM and Ellisen LW: Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol. 25:5834–5845. 2005. View Article : Google Scholar : PubMed/NCBI
13	Brugarolas J, Lei K, Hurley RL, et al: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18:2893–2904. 2004. View Article : Google Scholar : PubMed/NCBI
14	Shoshani T, Faerman A, Mett I, et al: Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol. 22:2283–2293. 2002. View Article : Google Scholar : PubMed/NCBI
15	Ellisen LW, Ramsayer KD, Johannessen CM, et al: REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell. 10:995–1005. 2002. View Article : Google Scholar : PubMed/NCBI
16	Yu S, Liu M, Gu X and Ding F: Neuroprotective effects of salidroside in the PC12 cell model exposed to hypoglycemia and serum limitation. Cell Mol Neurobiol. 28:1067–1078. 2008. View Article : Google Scholar : PubMed/NCBI
17	Zhang J, Liu A, Hou R, et al: Salidroside protects cardiomyocyte against hypoxia-induced death: a HIF-1 alpha-activated and VEGF-mediated pathway. Eur J Pharmacol. 607:6–14. 2009. View Article : Google Scholar : PubMed/NCBI
18	Nakayama H, Chen X, Baines CP, et al: Ca²⁺- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest. 117:2431–2444. 2007.
19	Buss SJ, Muenz S, Riffel JH, et al: Beneficial effects of mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol. 54:2435–2446. 2009. View Article : Google Scholar : PubMed/NCBI
20	Lajoie C, El-Helou V, Proulx C, Clément R, Gosselin H and Calderone A: Infarct size is increased in female post-MI rats treated with rapamycin. Can J Physiol Pharmacol. 87:460–470. 2009. View Article : Google Scholar : PubMed/NCBI
21	Zhang L, Ding W, Sun H, et al: Salidroside protects PC12 cells from MPP⁺-induced apoptosis via activation of the PI3K/Akt pathway. Food Chem Toxicol. 50:2591–2597. 2012. View Article : Google Scholar : PubMed/NCBI
22	Zhu Y, Shi YP, Wu D, et al: Salidroside protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via PI3K-Akt dependent pathway. DNA Cell Biol. 30:809–819. 2011. View Article : Google Scholar : PubMed/NCBI
23	DeYoung MP, Horak P, Sofer A, Sgroi D and Ellisen LW: Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 22:239–251. 2008. View Article : Google Scholar : PubMed/NCBI
24	Liu L, Cash TP, Jones RG, Keith B, Thompson CB and Simon MC: Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 21:521–531. 2006. View Article : Google Scholar : PubMed/NCBI
25	Hernández G, Lal H, Fidalgo M, et al: A novel cardioprotective p38-MAPK/mTOR pathway. Exp Cell Res. 317:2938–2949. 2011.PubMed/NCBI
26	Wang BH, Shravah J, Luo HL, Raedschelders K, Chen DD and Ansley DM: Propofol protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via Akt activation and Bcl-2 up-regulation. Biochem Biophys Res Commun. 389:105–111. 2009. View Article : Google Scholar : PubMed/NCBI
27	Miyamoto S, Murphy AN and Brown JH: Akt mediated mitochondrial protection in the heart: metabolic and survival pathways to the rescue. J Bioenerg Biomembr. 41:169–180. 2009. View Article : Google Scholar : PubMed/NCBI