Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction

Chen,Shuhua; Yang,Jie; Xiang,Hong; Chen,Wei; Zhong,Hua; Yang,Guoping; Fang,Ting; Deng,Hao; Yuan,Hong; Chen,Alex  F.; Lu,Hongwei

doi:10.3892/ijmm.2015.2100

Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction

Authors:
- Shuhua Chen
- Jie Yang
- Hong Xiang
- Wei Chen
- Hua Zhong
- Guoping Yang
- Ting Fang
- Hao Deng
- Hong Yuan
- Alex F. Chen
- Hongwei Lu
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Affiliations: Center for Experimental Medical Research, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: February 12, 2015 https://doi.org/10.3892/ijmm.2015.2100
Pages: 1103-1108

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Abstract

The hyperglycemia-induced production of oxidative stress results in endothelial cell dysfunction. Previous studies have demonstrated that sphingosine-1-phosphate (S1P) regulates an array of biological activities in endothelial cells mediated by sphingosine-1-phosphate receptors (S1PRs). However, the role of S1PR-mediated signaling pathways in hyperglycemia-induced endothelial cell dysfunction is currently unknown. In the present study, we aimed to explore the role of S1PRs in endothelial cell dysfunction. For this purpose, hyperglycemia-induced oxidative stress was examined using human umbilical vein endothelial cells (HUVECs) cultured with either normal (5.6 mM) or high (25 mM) levels of glucose. The levels of reactive oxygen species (ROS) and nitric oxide (NO) were determined by flow cytometric (FCM) analysis and nitrate reductase, respectively. Endothelial morphogenesis assay was performed in three-dimensional Matrigel. The mRNA and protein expression levels of S1PRs in the HUVECs were determined by RT-qPCR and western blot analysis, respectively. In addition, ROS, NO and endothelial morphogenesis assays were conducted using the high glucose-treated endothelial cells transfected with adenoviral vector expressing exogenous S1PR1 gene (pAd-S1PR1) or with adenoviral vector expressing S1PR2-specific shRNA (pAd-shRNA-S1PR2). The expression levels of S1PR1 and S1PR2 in the endothelial cells treated with high levels of glucose decreased and increased, respectively. However, the effects of high levels of glucose on S1PR3 were minimal. In addition, high levels of glucose enhanced ROS generation and markedly reduced NO generation and morphogenetic responses. Nevertheless, all the aforementioned changes were completely reversed by transfection with pAd-S1PR1 or pAd-shRNA-S1PR2, which increased S1PR1 and decreased S1PR2 expression, respectively. It can thus be concluded that S1PR1 and S1PR2 play crucial roles in hyperglycemia-induced endothelial cell dysfunction.

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1	Sena CM, Pereira AM and Seiça R: Endothelial dysfunction - a major mediator of diabetic vascular disease. Biochim Biophys Acta. 1832:2216–2231. 2013. View Article : Google Scholar : PubMed/NCBI
2	Wei DH, Zhang XL, Wang R, et al: Oxidized lipoprotein(a) increases endothelial cell monolayer permeability via ROS generation. Lipids. 48:579–586. 2013. View Article : Google Scholar : PubMed/NCBI
3	Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G and Nishigaki I: The vascular endo-thelium and human diseases. Int J Biol Sci. 10:1057–1069. 2013. View Article : Google Scholar
4	Li H, Horke S and Förstermann U: Oxidative stress in vascular disease and its pharmacological prevention. Trends Pharmacol Sci. 34:313–319. 2013. View Article : Google Scholar : PubMed/NCBI
5	Walker AE, Kaplon RE, Lucking SM, Russell-Nowlan MJ, Eckel RH and Seals DR: Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing endothelial nitric oxide synthase in healthy normolipidemic older adults. Hypertension. 60:1517–1523. 2012. View Article : Google Scholar : PubMed/NCBI
6	Lerman A and Zeiher AM: Endothelial function: cardiac events. Circulation. 111:363–368. 2005. View Article : Google Scholar : PubMed/NCBI
7	Paneni F, Osto E, Costantino S, et al: Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction. Circulation. 127:1229–1240. 2013. View Article : Google Scholar : PubMed/NCBI
8	Sharma S, Sun X, Agarwal S, Rafikov R, Dasarathy S, Kumar S and Black SM: Role of carnitine acetyl transferase in regulation of nitric oxide signaling in pulmonary arterial endothelial cells. Int J Mol Sci. 14:255–272. 2012. View Article : Google Scholar
9	Takuwa Y, Okamoto Y, Yoshioka K and Takuwa N: Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system. Biochim Biophys Acta. 1781:483–488. 2008. View Article : Google Scholar : PubMed/NCBI
10	Yatomi Y: Sphingosine 1-phosphate in vascular biology: possible therapeutic strategies to control vascular diseases. Curr Pharm Des. 12:575–587. 2006. View Article : Google Scholar : PubMed/NCBI
11	Spiegel S and Milstien S: Sphingosine 1-phosphate, a key cell signaling molecule. J Biol Chem. 227:25851–25854. 2002. View Article : Google Scholar
12	Rosen H, Stevens RC, Hanson M, Roberts E and Oldstone MB: Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. Annu Rev Biochem. 82:637–662. 2013. View Article : Google Scholar : PubMed/NCBI
13	Lu H, Yuan H, Chen S, et al: Senescent endothelial dysfunction is attributed to the up-regulation of sphingosine-1-phosphate receptor-2 in aged rats. Mol Cell Biochem. 363:217–224. 2012. View Article : Google Scholar
14	Lee JF, Gordon S, Estrada R, et al: Balance of S1P1 and S1P2 signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature. Am J Physiol Heart Circ Physiol. 296:H33–H42. 2009. View Article : Google Scholar :
15	Estrada R, Zeng Q, Lu H, et al: Up-regulating sphin-gosine-1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells. J Biol Chem. 283:30363–30375. 2008. View Article : Google Scholar : PubMed/NCBI
16	Liu W, Lan T, Xie X, et al: S1P2 receptor mediates sphin-gosine-1-phosphate-induced fibronectin expression via MAPK signaling pathway in mesangial cells under high glucose condition. Exp Cell Res. 318:936–943. 2012. View Article : Google Scholar : PubMed/NCBI
17	Takuwa N, Ohkura S, Takashima S, et al: S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. Cardiovasc Res. 85:484–493. 2010. View Article : Google Scholar :
18	Beckman JA, Creager MA and Libby P: Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 15:2570–2581. 2002. View Article : Google Scholar
19	Nesto RW: Correlation between cardiovascular disease and diabetes mellitus: current concepts. Am J Med. 116(Suppl 1): 11–22. 2004. View Article : Google Scholar
20	Félétou M and Vanhoutte PM: Endothelial dysfunction: a multifaceted disorder (the Wiggers award lecture). Am J Physiol Heart Circ Physiol. 291:H985–H1002. 2006. View Article : Google Scholar : PubMed/NCBI
21	Endemann DH and Schiffrin EL: Endothelial dysfunction. J Am Soc Nephrol. 15:1983–1992. 2004. View Article : Google Scholar : PubMed/NCBI
22	Wheatcroft SB, Williams IL, Shah AM and Kearney MT: Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med. 20:255–268. 2003. View Article : Google Scholar : PubMed/NCBI
23	Novella S, Dantas AP, Segarra G, et al: Aging-related endothelial dysfunction in the aorta from female senescence-accelerated mice is associated with decreased nitric oxide synthase expression. Exp Gerontol. 48:1329–1337. 2013. View Article : Google Scholar : PubMed/NCBI
24	Lesniewski LA, Zigler MC, Durrant JR, Donato AJ and Seals DR: Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism. Mech Ageing Dev. 133:368–371. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wilk G, Osmenda G, Matusik P, et al: Endothelial function assessment in atherosclerosis: comparison of brachial artery flow-mediated vasodilation and peripheral arterial tonometry. Pol Arch Med Wewn. 123:443–452. 2013.
26	Ragino YI, Chernjavski AM, Polonskaya YV, Volkov AM, Kashtanova EV, Tikhonov AV and Tcimbal SY: Oxidation and endothelial dysfunction biomarkers of atherosclerotic plaque instability. Studies of the vascular wall and blood. Bull Exp Biol Med. 153:331–335. 2012. View Article : Google Scholar : PubMed/NCBI
27	Lee S, Zhang H, Chen J, Dellsperger KC, Hill MA and Zhang C: Adiponectin abates diabetes-induced endothelial dysfunction by suppressing oxidative stress, adhesion molecules, and inflammation in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 303:H106–H115. 2012. View Article : Google Scholar : PubMed/NCBI
28	Cho YE, Basu A, Dai A, Heldak M and Makino A: Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice. Am J Physiol Cell Physiol. 305:C1033–C1040. 2013. View Article : Google Scholar : PubMed/NCBI
29	Shen GX: Mitochondrial dysfunction, oxidative stress and diabetic cardiovascular disorders. Cardiovasc Hematol Disord Drug Targets. 12:106–112. 2012. View Article : Google Scholar : PubMed/NCBI
30	Patel H, Chen J, Das KC and Kavdia M: Hyperglycemia induces differential change in oxidative stress at gene expression and functional levels in HUVEC and HMVEC. Cardiovasc Diabetol. 12:142–155. 2013. View Article : Google Scholar : PubMed/NCBI
31	Karbach S, Jansen T, Horke S, et al: Hyperglycemia and oxidative stress in cultured endothelial cells - a comparison of primary endothelial cells with an immortalized endothelial cell line. J Diabetes Complications. 26:155–162. 2012. View Article : Google Scholar : PubMed/NCBI
32	Liu Y, Saiyan S, Men TY, et al: Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors. J Pathol. 230:365–376. 2013. View Article : Google Scholar : PubMed/NCBI
33	Nakahara T, Iwase A, Nakamura T, et al: Sphingosine-1-phosphate inhibits H2O2-induced granulosa cell apoptosis via the PI3K/Akt signaling pathway. Fertil Steril. 98:1001–1008. 2012. View Article : Google Scholar : PubMed/NCBI
34	Krump-Konvalinkova V, Yasuda S, Rubic T, et al: Stable knockdown of the sphingosine 1-phosphate receptor S1P1 influences multiple functions of human endothelial cells. Arterioscler Thromb Vasc Biol. 25:546–552. 2005. View Article : Google Scholar
35	Whetzel AM, Bolick DT, Srinivasan S, Macdonald TL, Morris MA, Ley K and Hedrick CC: Sphingosine-1 phosphate prevents monocyte/endothelial interactions in type 1 diabetic NOD mice through activation of the S1P1 receptor. Circ Res. 99:731–739. 2006. View Article : Google Scholar : PubMed/NCBI
36	Whetzel AM, Bolick DT and Hedrick CC: Sphingosine-1-phosphate inhibits high glucose-mediated ERK1/2 action in endothelium through induction of MAP kinase phosphatase-3. Am J Physiol Cell Physiol. 296:C339–C345. 2009. View Article : Google Scholar :
37	Imasawa T, Kitamura H, Ohkawa R, Satoh Y, Miyashita A and Yatomi Y: Unbalanced expression of sphingosine 1-phosphate receptors in diabetic nephropathy. Exp Toxicol Pathol. 62:53–60. 2010. View Article : Google Scholar