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Article

High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs

  • Authors:
    • Qingbo Guan
    • Wen Liu
    • Yuantao Liu
    • Youfei Fan
    • Xiaolei Wang
    • Chunxiao Yu
    • Yuan Zhang
    • Shunke Wang
    • Jia Liu
    • Jiajun Zhao
    • Ling Gao
  • View Affiliations / Copyright

    Affiliations: Provincial Hospital affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, The Second Hospital of Shandong University, Jinan, Shandong 250021, P.R. China, Department of Cell Biology, Shandong University, Jinan, Shandong 250021, P.R. China
  • Pages: 810-814
    |
    Published online on: December 31, 2014
       https://doi.org/10.3892/ijmm.2014.2059
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Abstract

Hydrogen sulfide (H2S) has recently been identified as an endogenous gaseous signaling molecule. In the vascular system, the formation of H2S is catalyzed by cystathionine γ‑lyase (CSE). Previous studies have demonstrated the protective effects of H2S on ischemic injury in various types of tissue. However,, little is known about the role of H2S in diabetes-associated vascular diseases. Thus, the aim of the present study was to examine the possible role of H2S in high glucose-induced vascular dysfunction, and to explore the underlying mechanisms. Human umbilical vein endothelial cells (HUVECs) were isolated from human umbilical veins. The levels of H2S following treatment with various levels of glucose were determined and the secretion of endothelin-1 (ET-1) was measured by ELISA. The mRNA and protein expression of CSE in the HUVECs was determined by real-time RT-PCR and western blot analysis, respectively. Treatment with high glucose (25 mmol/l) for 48 h significantly increased the secretion of ET-1 by HUVECs, with the concomitant suppression of H2S production and CSE protein expression. The increase in exogenous H2S levels through the administration of sodium hydrosulfide (NaHS) attenuated the high glucose-induced downregulation of CSE protein expression, and significantly inhibited the secretion of ET-1. These results suggest that the downregulation of CSE protein expression and the subsequent decrease in H2S production play a role in high glucose-induced vascular dysfunction possibly by increasing the secretion of ET-1 by endothelial cells.
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1 

Grundy SM, Howard B, Smith S Jr, Eckel R, Redberg R and Bonow RO: Prevention Conference VI: Diabetes and Cardiovascular Disease: executive summary: conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation. 105:2231–2239. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Guangda X and Yuhua W: Apolipoprotein e4 allele and endothelium-dependent arterial dilation in Type 2 diabetes mellitus without angiopathy. Diabetologia. 46:514–519. 2003.PubMed/NCBI

3 

Lüscher TF and Vanhoutte PM: The Endothelium: Modulator of Cardiovascular Function. CRC Press; Boca Raton, FL: pp. 1–228. 1990

4 

Kharitonov VG, Sharma VS, Pilz RB, Magde D and Koesling D: Basis of guanylate cyclase activation by carbon monoxide. Proc Natl Acad Sci USA. 92:2568–2571. 1995. View Article : Google Scholar : PubMed/NCBI

5 

Yet SF, Tian R, Layne MD, et al: Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res. 89:168–173. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Wang R: Two’s company, three’s a crowd: can H S be the third endogenous gaseous transmitter? FASEB J. 16:17922–1798. 2002. View Article : Google Scholar

7 

Warenycia MW, Goodwin LR, Benishin CG, et al: Acute hydrogen sulfide poisoning. Demonstration of selective uptake of sulfide by the brainstem by measurement of brain sulfide levels. Biochem Pharmacol. 38:973–981. 1989. View Article : Google Scholar : PubMed/NCBI

8 

Abe K and Kimura H: The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 16:1066–1071. 1996.PubMed/NCBI

9 

Hosoki R, Matsuki N and Kimura H: The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 237:527–531. 1997. View Article : Google Scholar : PubMed/NCBI

10 

Shibuya N, Tanaka M, Yoshida M, et al: 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal. 11:703–714. 2009. View Article : Google Scholar

11 

Zhao W, Zhang J, Lu Y and Wang R: The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J. 20:6008–6016. 2001. View Article : Google Scholar : PubMed/NCBI

12 

Cheng Y, Ndisang JF, Tang G, Cao K and Wang R: Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats. Am J Physiol Heart Circ Physiol. 287:H2316–H2323. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Zhao W and Wang R: H2S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol. 283:H474–H480. 2002.PubMed/NCBI

14 

Yang G, Wu L, Jiang B, et al: H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gammalyase. Science. 322:587–590. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Johansen D, Ytrehus K and Baxter GF: Exogenous hydrogen sulfide (H2S) protects against regional myocardial ischemia-reperfusion injury - Evidence for a role of K ATP channels. Basic Res Cardiol. 101:53–60. 2006. View Article : Google Scholar

16 

Kimura H, Nagai Y, Umemura K and Kimura Y: Physiological roles of hydrogen sulfide: synaptic modulation, neuroprotection, and smooth muscle relaxation. Antioxid Redox Signal. 7:795–803. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Jha S, Calvert JW, Duranski MR, Ramachandran A and Lefer DJ: Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. Am J Physiol Heart Circ Physiol. 295:H801–H806. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Tripatara P, Patel NS, Collino M, et al: Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal ischemia/reperfusion injury and dysfunction. Lab Invest. 88:1038–1048. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Fu Z, Liu X, Geng B, Fang L and Tang C: Hydrogen sulfide protects rat lung from ischemia-reperfusion injury. Life Sci. 82:1196–1202. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Brancaleone V, Roviezzo F, Vellecco V, De Gruttola L, Bucci M and Cirino G: Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice. Br J Pharmacol. 155:673–680. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Whiteman M, Gooding KM, Whatmore JL, et al: Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia. 53:1722–1726. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Li L, Bhatia M, Zhu YZ, et al: Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB. 19:1196–1198. 2005.

23 

Lee M, Schwab C, Yu S, McGeer E and McGeer PL: Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide. Neurobiol Aging. 30:1523–1534. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Zhong G, Chen F, Cheng Y, Tang C and Du J: The role of hydrogen sulfide generation in the pathogenesis of hypertension in rats induced by inhibition of nitric oxide synthase. J Hypertens. 21:1879–1885. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Kimura Y and Kimura H: Hydrogen sulfide protects neurons from oxidative stress. FASEB J. 18:1165–1167. 2004.PubMed/NCBI

26 

Perini R, Fiorucci S and Wallace JL: Mechanisms of nonsteroidal anti-inflammatory drug-induced gastrointestinal injury and repair: a window of opportunity for cyclooxygenase-inhibiting nitric oxide donors. Can J Gastroenterol. 18:229–236. 2004.PubMed/NCBI

27 

Fiorucci S, Antonelli E, Distrutti E, et al: Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology. 129:1210–1224. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Li T, Zhao B, Wang C, et al: Regulatory effects of hydrogen sulfide on IL-6, IL-8 and IL-10 levels in the plasma and pulmonary tissue of rats with acute lung injury. Exp Biol Med. 233:1081–1087. 2008. View Article : Google Scholar

29 

Fang L, Li H, Tang C, Geng B, Qi Y and Liu X: Hydrogen sulfide attenuates the pathogenesis of pulmonary fibrosis induced by bleomycin in rats. Can J Physiol Pharmacol. 87:531–538. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Chen YH, Yao WZ, Geng B, et al: Endogenous hydrogen sulfide in patients with COPD. Chest. 128:3205–3211. 2005. View Article : Google Scholar : PubMed/NCBI

31 

Jiang HL, Wu HC, Li ZL, Geng B and Tang CS: Changes of the new gaseous transmitter H S in patients with coronary heart disease. Di Yi Jun Yi Da Xue Xue Bao. 25:951–954. 2005.In Chinese. PubMed/NCBI

32 

Chester AH: Endothelin-1 and the aortic valve. Curr Vasc Pharmacol. 3:353–357. 2005. View Article : Google Scholar : PubMed/NCBI

33 

Yanagisawa M, Kurihara H, Kimura S, et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 332:411–415. 1988. View Article : Google Scholar : PubMed/NCBI

34 

Quiñones MJ and Nicholas SB: Insulin resistance and the endothelium. Curr Diab Rep. 5:246–253. 2005. View Article : Google Scholar : PubMed/NCBI

35 

DeLoach S, Huan Y, Daskalakis C and Falkner B: Endothelin-1 response to glucose and insulin among African Americans. J Am Soc Hypertens. 4:227–235. 2010. View Article : Google Scholar : PubMed/NCBI

36 

Liu J, Wei S, Tian L, Yan L, Guo Q and Ma X: Effects of endomorphins on human umbilical vein endothelial cells under high glucose. Peptides. 32:86–92. 2011. View Article : Google Scholar

37 

Beauchamp RO Jr, Bus JS, Popp JA, Boreiko CJ and Andjelkovich DA: A critical review of the literature on hydrogen sulfide toxicity. Crit Rev Toxicol. 13:25–97. 1984. View Article : Google Scholar : PubMed/NCBI

38 

Li XH, Du JB and Tang CS: Impact of hydrogen sulfide donor on pulmonary vascular structure and vasoactive peptides in rats with pulmonary hypertension induced by high pulmonary blood flow. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 28:159–163. 2006.In Chinese. PubMed/NCBI

39 

Li X, Du J, Jin H, Geng B and Tang C: Sodium hydrosulfide alleviates pulmonary artery collagen remodeling in rats with high pulmonary blood flow. Heart Vessels. 23:409–419. 2008. View Article : Google Scholar : PubMed/NCBI

40 

Shaoqing Y, Ruxin Z, Yinjian C, Jianqiu C, Zhiqiang Y and Genhong L: Down-regulation of endogenous hydrogen sulphide pathway in nasal mucosa of allergic rhinitis in guinea pigs. Allergol Immunopathol. 37:180–187. 2009. View Article : Google Scholar

41 

Chang T, Untereiner A, Liu J and Wu L: Interaction of methylglyoxal and hydrogen sulfide in rat vascular smooth muscle cells. Antioxid Redox Signal. 12:1093–1100. 2010. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Guan Q, Liu W, Liu Y, Fan Y, Wang X, Yu C, Zhang Y, Wang S, Liu J, Zhao J, Zhao J, et al: High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs. Int J Mol Med 35: 810-814, 2015.
APA
Guan, Q., Liu, W., Liu, Y., Fan, Y., Wang, X., Yu, C. ... Gao, L. (2015). High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs. International Journal of Molecular Medicine, 35, 810-814. https://doi.org/10.3892/ijmm.2014.2059
MLA
Guan, Q., Liu, W., Liu, Y., Fan, Y., Wang, X., Yu, C., Zhang, Y., Wang, S., Liu, J., Zhao, J., Gao, L."High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs". International Journal of Molecular Medicine 35.3 (2015): 810-814.
Chicago
Guan, Q., Liu, W., Liu, Y., Fan, Y., Wang, X., Yu, C., Zhang, Y., Wang, S., Liu, J., Zhao, J., Gao, L."High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs". International Journal of Molecular Medicine 35, no. 3 (2015): 810-814. https://doi.org/10.3892/ijmm.2014.2059
Copy and paste a formatted citation
x
Spandidos Publications style
Guan Q, Liu W, Liu Y, Fan Y, Wang X, Yu C, Zhang Y, Wang S, Liu J, Zhao J, Zhao J, et al: High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs. Int J Mol Med 35: 810-814, 2015.
APA
Guan, Q., Liu, W., Liu, Y., Fan, Y., Wang, X., Yu, C. ... Gao, L. (2015). High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs. International Journal of Molecular Medicine, 35, 810-814. https://doi.org/10.3892/ijmm.2014.2059
MLA
Guan, Q., Liu, W., Liu, Y., Fan, Y., Wang, X., Yu, C., Zhang, Y., Wang, S., Liu, J., Zhao, J., Gao, L."High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs". International Journal of Molecular Medicine 35.3 (2015): 810-814.
Chicago
Guan, Q., Liu, W., Liu, Y., Fan, Y., Wang, X., Yu, C., Zhang, Y., Wang, S., Liu, J., Zhao, J., Gao, L."High glucose induces the release of endothelin-1 through the inhibition of hydrogen sulfide production in HUVECs". International Journal of Molecular Medicine 35, no. 3 (2015): 810-814. https://doi.org/10.3892/ijmm.2014.2059
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