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Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells

  • Authors:
    • Ying He
    • Zhou Luan
    • Xunan Fu
    • Xun Xu
  • View Affiliations / Copyright

    Affiliations: Department of Ophthalmology, The Central Hospital of Wuhan, Wuhan, Hubei 430014, P.R. China, Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Ophthalmology, Shanghai First Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
    Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 631-638
    |
    Published online on: February 3, 2016
       https://doi.org/10.3892/ijmm.2016.2478
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Abstract

Ectopic apoptosis of vascular cells plays a critical role in the early stage development of diabetic retinopathy (DR). Uncoupling protein 2 (UCP2) is a mitochondrial modulator which protects against endothelial dysfunction. However, the role which UCP2 plays in endothelial apoptosis and its association with DR was unclear. In the present study, we investigated whether UCP2 functioned as an inhibitor of DR in endothelial cells. Firstly, we noted that in UCP2‑knockout mice retinal cell death and damage in vivo was similar to that of db/db diabetic mice. Additionally, UCP2 knockdown induced caspase-3 activation and exaggerated high glucose (HG)-induced apoptosis of human umbilical vein endothelial cells (HUVECs). Conversely, adenovirus-mediated UCP2 overexpression inhibited the apoptosis of HUVECs and HG-induced caspase-3 activation. Furthermore, HG treatment resulted in the opening of the permeability transition pore (PTP) and liberation of cytochrome c from mitochondria to the cytosol in HUVECs. Notably, UCP2 overexpression inhibited these processes. Furthermore, adenovirus-mediated UCP2 overexpression led to a significant increase in intracellular nitric oxide (NO) levels and a decrease in reactive oxygen species (ROS) generation in HUVECs. Collectively, these data suggest that UCP2 plays an anti-apoptotic role in endothelial cells. Thus, we suggest that approaches which augment UCP2 expression in vascular endothelial cells aid in preventing the early stage development and progression of DR.
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1 

Cerani A, Tetreault N, Menard C, Lapalme E, Patel C, Sitaras N, Beaun F, Leboeuf D, De Guire V, Binet F, et al: Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1. Cell Metab. 18:505–518. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Barot M, Gokulgandhi MR, Patel S and Mitra AK: Microvascular complications and diabetic retinopathy: recent advances and future implications. Future Med Chem. 5:301–314. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, Aiello LP, Kern TS and King GL: Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med. 15:1298–1306. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Jiang Y, Zhang Q, Soderland C and Steinle JJ: TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. Cell Signal. 24:1086–1092. 2012. View Article : Google Scholar : PubMed/NCBI

5 

Montero JA, Ruiz-Moreno JM and Correa ME: Intravitreal anti-VEGF drugs as adjuvant therapy in diabetic retinopathy surgery. Curr Diabetes Rev. 7:176–184. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Hammes HP, Feng Y, Pfister F and Brownlee M: Diabetic retinopathy: targeting vasoregression. Diabetes. 60:9–16. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Bressler NM, Beck RW and Ferris FL III: Panretinal photocoagulation for proliferative diabetic retinopathy. N Engl J Med. 365:1520–1526. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Zhang CY, Parton LE, Ye CP, Krauss S, Shen R, Lin CT, Porco JA Jr and Lowell BB: Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab. 3:417–427. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Brand MD and Esteves TC: Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab. 2:85–93. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Bouillaud F: UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing. Biochim Biophys Acta. 1787:377–383. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Wilkinson-Berka JL, Rana I, Armani R and Agrotis A: Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy. Clin Sci (Lond). 124:597–615. 2013. View Article : Google Scholar

12 

Zheng Z, Chen H, Ke G, Fan Y, Zou H, Sun X, Gu Q, Xu X and Ho PC: Protective effect of perindopril on diabetic retinopathy is associated with decreased vascular endothelial growth factor-to-pigment epithelium-derived factor ratio: involvement of a mitochondria-reactive oxygen species pathway. Diabetes. 58:954–964. 2009. View Article : Google Scholar : PubMed/NCBI

13 

He Y, Wang N, Shen Y, Zheng Z and Xu X: Inhibition of high glucose-induced apoptosis by UCP2 in human umbilical vein endothelial cells. Int J Mol Med. 33:1275–1281. 2014.PubMed/NCBI

14 

Luan Z, He Y, Alattar M, Chen Z and He F: Targeting the prohibitin scaffold-CRAF kinase interaction in RAS-ERK-driven pancreatic ductal adenocarcinoma. Mol Cancer. 13:382014. View Article : Google Scholar : PubMed/NCBI

15 

Zorov DB, Filburn CR, Klotz LO, Zweier JL and Sollott SJ: Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med. 192:1001–1014. 2000. View Article : Google Scholar : PubMed/NCBI

16 

Hausenloy DJ and Yellon DM: The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol. 35:339–341. 2003. View Article : Google Scholar : PubMed/NCBI

17 

Davidson SM, Hausenloy D, Duchen MR and Yellon DM: Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem Cell Biol. 38:414–419. 2006. View Article : Google Scholar

18 

Lim SY, Davidson SM, Paramanathan AJ, Smith CC, Yellon DM and Hausenloy DJ: The novel adipocytokine visfatin exerts direct cardioprotective effects. J Cell Mol Med. 12:1395–1403. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Bass DA, Parce JW, Dechatelet LR, Szejda P, Seeds MC and Thomas M: Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol. 130:1910–1917. 1983.PubMed/NCBI

20 

van Reyk DM, King NJ, Dinauer MC and Hunt NH: The intracellular oxidation of 2′,7′-dichlorofluorescin in murine T lymphocytes. Free Radic Biol Med. 30:82–88. 2001. View Article : Google Scholar : PubMed/NCBI

21 

Shao C, Stewart V, Folkard M, Michael BD and Prise KM: Nitric oxide-mediated signaling in the bystander response of individually targeted glioma cells. Cancer Res. 63:8437–8442. 2003.PubMed/NCBI

22 

Jezek P and Garlid KD: Mammalian mitochondrial uncoupling proteins. Int J Biochem Cell Biol. 30:1163–1168. 1998. View Article : Google Scholar : PubMed/NCBI

23 

Derdak Z, Mark NM, Beldi G, Robson SC, Wands JR and Baffy G: The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res. 68:2813–2819. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Baffy G: Uncoupling protein-2 and cancer. Mitochondrion. 10:243–252. 2010. View Article : Google Scholar

25 

Williams IL, Wheatcroft SB, Shah AM and Kearney MT: Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. Int J Obes Relat Metab Disord. 26:754–764. 2002.PubMed/NCBI

26 

Bhattacharjee PS, Huq TS, Potter V, Young A, Davenport IR, Graves R, Mandal TK, Clement C, McFerrin HE, Muniru-zzaman S, et al: High-glucose-induced endothelial cell injury is inhibited by a peptide derived from human apolipoprotein E. PLoS One. 7:e521522012. View Article : Google Scholar

27 

Titchenell PM and Antonetti DA: Using the past to inform the future: anti-VEGF therapy as a road map to develop novel therapies for diabetic retinopathy. Diabetes. 62:1808–1815. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Ababneh OH, Yousef YA, Gharaibeh AM, Abu Ameerh MA, Abu-Yaghi NE and Al Bdour MD: Intravitreal bevacizumab in the treatment of diabetic ocular neovascularization. Retina. 33:748–755. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Verma A, Shan Z, Lei B, Yuan L, Liu X, Nakagawa T, Grant MB, Lewin AS, Hauswirth WW, Raizada MK and Li Q: ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. Mol Ther. 20:28–36. 2012. View Article : Google Scholar :

30 

Zhang Z, Meng X, Wu Z, Zou W, Zhang J, Zhu D, Chen T and Zhang Q: Changes in choroidal thickness after panretinal photocoagulation for diabetic retinopathy: a 12-week longitudinal study. Invest Ophthalmol Sci. 56:2631–2638. 2015. View Article : Google Scholar

31 

Kumar B, Gupta SK, Saxena R and Srivastava S: Current trends in the pharmacotherapy of diabetic retinopathy. J Postgrad Med. 58:132–139. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Liu BC, Chen Q, Luo DD, Sun J, Phillips AO, Ruan XZ and Liu NF: Mechanisms of irbesartan in prevention of renal lesion in streptozotocin-induced diabetic rats. Acta Pharmacol Sin. 24:67–73. 2003.PubMed/NCBI

33 

Devi TS, Hosoya K, Terasaki T and Singh LP: Critical role of TXNIP in oxidative stress, DNA damage and retinal pericyte apoptosis under high glucose: implications for diabetic retinopathy. Exp Cell Res. 319:1001–1012. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Rask-Madsen C and King GL: Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 17:20–33. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Fu D, Wu M, Zhang J, Du M, Yang S, Hammad SM, Wilson K, Chen J and Lyons TJ: Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy. Diabetologia. 55:3128–3140. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Kowluru RA, Mohammad G, dos Santos JM and Zhong Q: Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage. Diabetes. 60:3023–3033. 2011. View Article : Google Scholar : PubMed/NCBI

37 

Tyas L, Brophy VA, Pope A, Rivett AJ and Tavaré JM: Rapid caspase-3 activation during apoptosis revealed using fluorescence-resonance energy transfer. EMBO Rep. 1:266–270. 2000. View Article : Google Scholar

38 

Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF, Melcher T, Gonzalez-Zulueta M, et al: Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med. 9:1062–1068. 2003. View Article : Google Scholar : PubMed/NCBI

39 

Tian XY, Wong WT, Xu A, Lu Y, Zhang Y, Wang L, Cheang WS, Wang Y, Yao X and Huang Y: Uncoupling protein-2 protects endothelial function in diet-induced obese mice. Circ Res. 110:1211–1216. 2012. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
He Y, Luan Z, Fu X and Xu X: Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells. Int J Mol Med 37: 631-638, 2016.
APA
He, Y., Luan, Z., Fu, X., & Xu, X. (2016). Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells. International Journal of Molecular Medicine, 37, 631-638. https://doi.org/10.3892/ijmm.2016.2478
MLA
He, Y., Luan, Z., Fu, X., Xu, X."Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells". International Journal of Molecular Medicine 37.3 (2016): 631-638.
Chicago
He, Y., Luan, Z., Fu, X., Xu, X."Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells". International Journal of Molecular Medicine 37, no. 3 (2016): 631-638. https://doi.org/10.3892/ijmm.2016.2478
Copy and paste a formatted citation
x
Spandidos Publications style
He Y, Luan Z, Fu X and Xu X: Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells. Int J Mol Med 37: 631-638, 2016.
APA
He, Y., Luan, Z., Fu, X., & Xu, X. (2016). Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells. International Journal of Molecular Medicine, 37, 631-638. https://doi.org/10.3892/ijmm.2016.2478
MLA
He, Y., Luan, Z., Fu, X., Xu, X."Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells". International Journal of Molecular Medicine 37.3 (2016): 631-638.
Chicago
He, Y., Luan, Z., Fu, X., Xu, X."Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells". International Journal of Molecular Medicine 37, no. 3 (2016): 631-638. https://doi.org/10.3892/ijmm.2016.2478
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