Deferasirox inhibits lipid peroxidation and ferroptosis in human retinal endothelial cells_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Yan ^1,2 , Cheng Zixuan ¹ , Luo Ting ² ,  Lyu Hongbin ¹

1. Department of Ophthalmology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China;
2. Department of Ophthalmology, the People’s Hospital of Jianyang, Chengdu 641400, China;

Corresponding author：

Lyu Hongbin, Email: oculistlvhongbin@swmu.edu.cn

Keywords：

Retinal vascular endothelial cell; Diabetic retinopathy; Deferasirox; Ferroptosis; Lipid peroxidation; Cell experiment

DOI：

10.3760/cma.j.cn511434-20240701-00243

Video：

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Objective To observe and preliminarily explore the effects of Deferasirox (DFX) on lipid peroxidation and ferroptosis in human retinal endothelial cells (HREC). Methods A c ell experimental study. Divided the in vitro cultured HREC into normal glucose (NG) group, high glucose (HG) group, normal glucose+DFX (NG+DFX) group, high glucose+DFX (HG+DFX) group, normal glucose+DFX+FAC (NG+DFX+FAC) group, and high glucose+DFX+FAC (HG+DFX+FAC) group. Light microscope was used to observe the morphology of the cells; cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay, and Calcein-AM staining was used to detect the unstable iron pool (LIP) content, Fluorescent enzyme-linked immunosorbent assay reader was used to detect the reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and oxidized glutathione (GSSG); Western blot was used to detect the expression levels of Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11). Two-tailed Student t test was used for comparison between the two groups; one-way ANOVA was used for comparison between multiple groups. Results Compared with the HG group and the HG+DFX+FAC group, the cell proliferation rate and the contents of GSH, GPX4, and SLC7A11 in the HG+DFX group were significantly increased, and the differences were statistically significant (F=150.70, 21.02, 26.09, 52.62; P＜0.001). The contents of LIP, ROS, MDA, and GSSG were significantly decreased, and the differences were statistically significant (F=807.2, 16.94, 31.62, 19.21; P＜0.001). Conclusions High glucose significantly induces an increase in LIP, lipid peroxidation, and ferroptosis in HREC. Deferasirox inhibits lipid peroxidation and ferroptosis in HREC by downregulating LIP levels.

1.	Thomas RL, Halim S, Gurudas S, et al. IDF diabetes atlas: a review of studies utilising retinal photography on the global prevalence of diabetes related retinopathy between 2015 and 2018[J/OL]. Diabetes Res Clin Pract, 2019, 157: 107840[2019-11-14]. https://pubmed.ncbi.nlm.nih.gov/31733978/. DOI: 10.1016/j.diabres.2019.107840.
2.	Perais J, Agarwal R, Evans JR, et al. Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy[J/OL]. Cochrane Database Syst Rev, 2023, 2: CD013775[2023-02-22]. https://pubmed.ncbi.nlm.nih.gov/36815723/. DOI: 10.1002/14651858.CD013775.pub2.
3.	Liu K, Li H, Wang F, et al. Ferroptosis: mechanisms and advances in ocular diseases[J]. Mol Cell Biochem, 2023, 478: 2081-2095. DOI: 10.1007/s11010-022-04644-5.
4.	Li SY, Zhao N, Wei D, et al. Ferroptosis in the ageing retina: a malevolent fire of diabetic retinopathy[J/OL]. Ageing Res Rev, 2024, 93: 102142[2023-11-28]. https://pubmed.ncbi.nlm.nih.gov/38030091/. DOI: 10.1016/j.arr.2023.102142.
5.	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149: 1060-1072. DOI: 10.1016/j.cell.2012.03.042.
6.	Yan HF, Zou T, Tuo QZ, et al. Ferroptosis: mechanisms and links with diseases[J]. Signal Transduct Target Ther, 2021, 6(1): 49. DOI: 10.1038/s41392-020-00428-9.
7.	Tang W, Guo J, Liu W, et al. Ferrostatin-1 attenuates ferroptosis and protects the retina against light-induced retinal degeneration[J]. Biochem Biophys Res Commun, 2021, 548: 27-34. DOI: 10.1016/j.bbrc.2021.02.055.
8.	Chaudhary K, Promsote W, Ananth S, et al. Iron overload accelerates the progression of diabetic retinopathy in association with increased retinal renin expression[J/OL]. Sci Rep, 2018, 8(1): 3025[2018-02-14]. https://pubmed.ncbi.nlm.nih.gov/29445185/. DOI: 10.1038/s41598-018-21276-2.
9.	Song D, Dunaief JL, et al. Retinal iron homeostasis in health and disease[J/OL]. Front Aging Neurosci, 2013, 5: 24[2013-06-28]. https://pubmed.ncbi.nlm.nih.gov/23825457/. DOI: 10.3389/fnagi.2013.00024.
10.	Wu W, Geng Z, Bai H, et al. Ammonium ferric citrate induced ferroptosis in non-small-cell lung carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity[J]. Int J Med Sci, 2021, 18(8): 1899-1909. DOI: 10.7150/ijms.54860.
11.	Rudraraju M, Narayanan SP, Somanath PR, et al. Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy[J/OL]. Pharmacol Res, 2020, 161: 105115[2020-08-01]. https://pubmed.ncbi.nlm.nih.gov/32750417/. DOI: 10.1016/j.phrs.2020.105115.
12.	Qin Q, Yu N, Gu Y, et al. Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury[J]. Cell Death Dis, 2022, 13(5): 507. DOI: 10.1038/s41419-022-04911-9.
13.	Zhang J, Qiu Q, Wang H, et al. TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination[J/OL]. Exp Cell Res, 2021, 407(2): 112800[2021-10-15]. https://pubmed.ncbi.nlm.nih.gov/34487731/. DOI: 10.1016/j.yexcr.2021.112800.
14.	Ayala A, Muñoz MF, Argüelles S, et al. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal[J/OL]. Oxid Med Cell Longev, 2014, 2014: 360438[2014-05-08]. https://pubmed.ncbi.nlm.nih.gov/24999379/. DOI: 10.1155/2014/360438.
15.	Chai YC, Mieyal JJ. Glutathione and glutaredoxin-key players in cellular redox homeostasis and signaling[J]. Antioxidants (Basel, Switzerland), 2023, 12(8): 1553. DOI: 10.3390/antiox12081553.
16.	Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16: 1180-1191. DOI: 10.1038/ncb3064.
17.	Koppula P, Zhuang L, Gan B, et al. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12: 599-620. DOI: 10.1007/s13238-020-00789-5.
18.	Imai T, Tsuji S, Matsubara H, et al. Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models[J]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(1): 73-84. DOI: 10.1007/s00210-020-01963-6.
19.	Zhang XD, Liu ZY, Wang MS, et al. Mechanisms and regulations of ferroptosis[J/OL]. Front Immunol, 2023, 14: 1269451[2023-10-06]. https://pubmed.ncbi.nlm.nih.gov/37868994/. DOI: 10.3389/fimmu.2023.1269451.

1. Thomas RL, Halim S, Gurudas S, et al. IDF diabetes atlas: a review of studies utilising retinal photography on the global prevalence of diabetes related retinopathy between 2015 and 2018[J/OL]. Diabetes Res Clin Pract, 2019, 157: 107840[2019-11-14]. https://pubmed.ncbi.nlm.nih.gov/31733978/. DOI: 10.1016/j.diabres.2019.107840.
2. Perais J, Agarwal R, Evans JR, et al. Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy[J/OL]. Cochrane Database Syst Rev, 2023, 2: CD013775[2023-02-22]. https://pubmed.ncbi.nlm.nih.gov/36815723/. DOI: 10.1002/14651858.CD013775.pub2.
3. Liu K, Li H, Wang F, et al. Ferroptosis: mechanisms and advances in ocular diseases[J]. Mol Cell Biochem, 2023, 478: 2081-2095. DOI: 10.1007/s11010-022-04644-5.
4. Li SY, Zhao N, Wei D, et al. Ferroptosis in the ageing retina: a malevolent fire of diabetic retinopathy[J/OL]. Ageing Res Rev, 2024, 93: 102142[2023-11-28]. https://pubmed.ncbi.nlm.nih.gov/38030091/. DOI: 10.1016/j.arr.2023.102142.
5. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149: 1060-1072. DOI: 10.1016/j.cell.2012.03.042.
6. Yan HF, Zou T, Tuo QZ, et al. Ferroptosis: mechanisms and links with diseases[J]. Signal Transduct Target Ther, 2021, 6(1): 49. DOI: 10.1038/s41392-020-00428-9.
7. Tang W, Guo J, Liu W, et al. Ferrostatin-1 attenuates ferroptosis and protects the retina against light-induced retinal degeneration[J]. Biochem Biophys Res Commun, 2021, 548: 27-34. DOI: 10.1016/j.bbrc.2021.02.055.
8. Chaudhary K, Promsote W, Ananth S, et al. Iron overload accelerates the progression of diabetic retinopathy in association with increased retinal renin expression[J/OL]. Sci Rep, 2018, 8(1): 3025[2018-02-14]. https://pubmed.ncbi.nlm.nih.gov/29445185/. DOI: 10.1038/s41598-018-21276-2.
9. Song D, Dunaief JL, et al. Retinal iron homeostasis in health and disease[J/OL]. Front Aging Neurosci, 2013, 5: 24[2013-06-28]. https://pubmed.ncbi.nlm.nih.gov/23825457/. DOI: 10.3389/fnagi.2013.00024.
10. Wu W, Geng Z, Bai H, et al. Ammonium ferric citrate induced ferroptosis in non-small-cell lung carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity[J]. Int J Med Sci, 2021, 18(8): 1899-1909. DOI: 10.7150/ijms.54860.
11. Rudraraju M, Narayanan SP, Somanath PR, et al. Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy[J/OL]. Pharmacol Res, 2020, 161: 105115[2020-08-01]. https://pubmed.ncbi.nlm.nih.gov/32750417/. DOI: 10.1016/j.phrs.2020.105115.
12. Qin Q, Yu N, Gu Y, et al. Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury[J]. Cell Death Dis, 2022, 13(5): 507. DOI: 10.1038/s41419-022-04911-9.
13. Zhang J, Qiu Q, Wang H, et al. TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination[J/OL]. Exp Cell Res, 2021, 407(2): 112800[2021-10-15]. https://pubmed.ncbi.nlm.nih.gov/34487731/. DOI: 10.1016/j.yexcr.2021.112800.
14. Ayala A, Muñoz MF, Argüelles S, et al. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal[J/OL]. Oxid Med Cell Longev, 2014, 2014: 360438[2014-05-08]. https://pubmed.ncbi.nlm.nih.gov/24999379/. DOI: 10.1155/2014/360438.
15. Chai YC, Mieyal JJ. Glutathione and glutaredoxin-key players in cellular redox homeostasis and signaling[J]. Antioxidants (Basel, Switzerland), 2023, 12(8): 1553. DOI: 10.3390/antiox12081553.
16. Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16: 1180-1191. DOI: 10.1038/ncb3064.
17. Koppula P, Zhuang L, Gan B, et al. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12: 599-620. DOI: 10.1007/s13238-020-00789-5.
18. Imai T, Tsuji S, Matsubara H, et al. Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models[J]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(1): 73-84. DOI: 10.1007/s00210-020-01963-6.
19. Zhang XD, Liu ZY, Wang MS, et al. Mechanisms and regulations of ferroptosis[J/OL]. Front Immunol, 2023, 14: 1269451[2023-10-06]. https://pubmed.ncbi.nlm.nih.gov/37868994/. DOI: 10.3389/fimmu.2023.1269451.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesDeferasirox inhibits lipid peroxidation and ferroptosis in human retinal endothelial cells

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