Research progress between ferroptosis and vascular calcification_West China Medical Journal

Authors：

CAO Mengxia ^1,2,3 ,  OU Santao ^1,2,3

1. Department of Nephrology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
2. Sichuan Clinical Research Center for Nephrology, Luzhou, Sichuan 646000, P. R. China;
3. Sichuan Key Laboratory of Metabolic Vascular Diseases, Luzhou, Sichuan 646000, P. R. China;

Corresponding author：

OU Santao, Email: ousantao@163.com

Keywords：

Ferroptosis; vascular calcification; lipid peroxidation; iron overload

DOI：

10.7507/1002-0179.202210004

Video：

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Vascular calcification is an active, adjustable and complex biological process. It is an independent hazard factor for cardiovascular events and there is a lack of effective treatment. As a newly discovered regulated cell death, ferroptosis is closely related to iron metabolism, lipid metabolism, glutathione metabolism and so on. In recent years, studies have shown that ferroptosis may be implicated in the occurrence and progression of vascular calcification. Based on the introduction of ferroptosis, this review will discuss the close relationship between ferroptosis and vascular calcification from intimal calcification, medial calcification and heart valve calcification, in order to provide new ideas for the prevention and treatment of vascular calcification.

Citation： CAO Mengxia, OU Santao. Research progress between ferroptosis and vascular calcification. West China Medical Journal, 2023, 38(3): 470-475. doi: 10.7507/1002-0179.202210004 Copy

1.	Quaglino D, Boraldi F, Lofaro FD. The biology of vascular calcification. Int Rev Cell Mol Biol, 2020, 354: 261-353.
2.	董谦谦, 颜建云. 血管钙化参与细胞相关研究的新进展. 中国动脉硬化杂志, 2018, 26(11): 1111-1115.
3.	Lee SJ, Lee IK, and Jeon JH. Vascular calcification-new insights into its mechanism. Int J Mol Sci, 2020, 21(8): 2685.
4.	Xia J, Si H, Yao W, et al. Research progress on the mechanism of ferroptosis and its clinical application. Exp Cell Res, 2021, 409(2): 112932.
5.	Li M, Wang ZW, Fang LJ, et al. Programmed cell death in atherosclerosis and vascular calcification. Cell Death Dis, 2022, 13(5): 467.
6.	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
7.	Xie B and Guo Y. Molecular mechanism of cell ferroptosis and research progress in regulation of ferroptosis by noncoding RNAs in tumor cells. Cell Death Discov, 2021, 7(1): 101.
8.	Hu CT, Shao YD, Liu YZ, et al. Oxidative stress in vascular calcification. Clin Chim Acta, 2021, 519: 101-110.
9.	陈正东, 刘乃丰. 铁稳态在血管钙化发病机制中的作用. 中国动脉硬化杂志, 2022, 30(7): 553-559.
10.	Sousa L, Oliveira MM, Pessôa MTC, et al. Iron overload: effects on cellular biochemistry. Clin Chim Acta, 2020, 504: 180-189.
11.	Gammella E, Recalcati S, Rybinska I, et al. Iron-induced damage in cardiomyopathy: oxidative-dependent and independent mechanisms. Oxid Med Cell Longev, 2015, 2015: 230182.
12.	Sun X, Ou Z, Xie M, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene, 2015, 34(45): 5617-5625.
13.	Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol, 2017, 13(1): 91-98.
14.	Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol, 2017, 13(1): 81-90.
15.	Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2): 273-285.
16.	Ma TL, Chen JX, Zhu P, et al. Focus on ferroptosis regulation: exploring novel mechanisms and applications of ferroptosis regulator. Life Sci, 2022, 307: 120868.
17.	Fan Z, Wirth AK, Chen D, et al. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis, 2017, 6(8): e371.
18.	Dodson M, Castro-Portuguez R, and Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol, 2019, 23: 101107.
19.	Zhao Y, Lu J, Mao A, et al. Autophagy inhibition plays a protective role in ferroptosis induced by alcohol via the p62-Keap1-Nrf2 pathway. J Agric Food Chem, 2021, 69(33): 9671-9683.
20.	He L, Liu YY, Wang K, et al. Tanshinone ⅡA protects human coronary artery endothelial cells from ferroptosis by activating the NRF2 pathway. Biochem Biophys Res Commun, 2021, 575: 1-7.
21.	Liu J, Kuang F, Kroemer G, et al. Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem Biol, 2020, 27(4): 420-435.
22.	Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol, 2020, 66: 89-100.
23.	Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature, 2019, 575(7784): 688-692.
24.	Leu JI, Murphy ME, and George DL. P53 regulates cellular redox state, ferroptosis and metabolism. Mol Cell Oncol, 2021, 8(2): 1877076.
25.	Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol, 2016, 26(3): 165-176.
26.	Hayano M, Yang WS, Corn CK, et al. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ, 2016, 23(2): 270-278.
27.	Battaglia AM, Chirillo R, Aversa I, et al. Ferroptosis and cancer: mitochondria meet the “iron maiden” cell death. Cells, 2020, 9(6): 1505.
28.	Ouyang S, You J, Zhi C, et al. Ferroptosis: the potential value target in atherosclerosis. Cell Death Dis, 2021, 12(8): 782.
29.	许杰, 杨剑峰, 何杨. 铁代谢在动脉粥样硬化中的研究进展. 临床心血管病杂志, 2020, 36(6): 506-509.
30.	黄紫霞, 吴明月, 许峰, 等. 柴胡皂苷 A 通过抑制氧化应激和铁死亡减轻过氧化氢诱导的人脐静脉内皮细胞损伤. 中国动脉硬化杂志, 2022, 30(1): 43-48.
31.	Marques VB, Leal MAS, Mageski JGA, et al. Chronic iron overload intensifies atherosclerosis in apolipoprotein E deficient mice: role of oxidative stress and endothelial dysfunction. Life Sci, 2019, 233: 116702.
32.	Vinchi F, Porto G, Simmelbauer A, et al. Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction. Eur Heart J, 2020, 41(28): 2681-2695.
33.	Bai T, Li M, Liu Y, et al. Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med, 2020, 160: 92-102.
34.	Li Q, Liu C, Deng L, et al. Novel function of fluvastatin in attenuating oxidized low-density lipoprotein-induced endothelial cell ferroptosis in a glutathione peroxidase4- and cystine-glutamate antiporter-dependent manner. Exp Ther Med, 2021, 22(5): 1275.
35.	刘洋, 孙岳, 杨安宁, 等. 铁死亡参与高脂饮食诱导的 ApoE^-/-小鼠动脉粥样硬化及 ox-LDL 诱导的泡沫细胞形成过程. 实用医学杂志, 2021, 37(5): 585-590.
36.	Su G, Yang W, Wang S, et al. SIRT1-autophagy axis inhibits excess iron-induced ferroptosis of foam cells and subsequently increases IL-1Beta and IL-18. Biochem Biophys Res Commun, 2021, 561: 33-39.
37.	Peng Q, Liu H, Luo Z, et al. Effect of autophagy on ferroptosis in foam cells via Nrf2. Mol Cell Biochem, 2022, 477(5): 1597-1606.
38.	Yang Z, Shi J, Chen L, et al. Role of pyroptosis and ferroptosis in the progression of atherosclerotic plaques. Front Cell Dev Biol, 2022, 10: 811196.
39.	Al Hariri M, Zibara K, Farhat W, et al. Cigarette smoking-induced cardiac hypertrophy, vascular inflammation and injury are attenuated by antioxidant supplementation in an animal model. Front Pharmacol, 2016, 7: 397.
40.	Sampilvanjil A, Karasawa T, Yamada N, et al. Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol, 2020, 318(3): H508-H518.
41.	Ma WQ, Sun XJ, Zhu Y, et al. Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects. Free Radic Biol Med, 2021, 165: 229-242.
42.	黄辉. 血管钙化的基础和转化研究的探索. 中山大学学报(医学科学版), 2017, 38(2): 184-188,214.
43.	Ren SC, Mao N, Yi S, et al. Vascular calcification in chronic kidney disease: an update and perspective. Aging Dis, 2022, 13(3): 673-697.
44.	Seto T, Hamada C, and Tomino Y. Suppressive effects of iron overloading on vascular calcification in uremic rats. J Nephrol, 2014, 27(2): 135-142.
45.	Ciceri P, Elli F, Braidotti P, et al. Iron citrate reduces high phosphate-induced vascular calcification by inhibiting apoptosis. Atherosclerosis, 2016, 254: 93-101.
46.	Wang P, Guo C, Pan H, et al. Iron Sucrose: a double-edged sword in high phosphate media-induced vascular calcification. Calcif Tissue Int, 2021, 108(6): 798-807.
47.	Kawada S, Nagasawa Y, Kawabe M, et al. Iron-induced calcification in human aortic vascular smooth muscle cells through interleukin-24 (IL-24), with / without TNF-alpha. Sci Rep, 2018, 8(1): 658.
48.	Zhao L, Yang N, Song Y, et al. Effect of iron overload on endothelial cell calcification and its mechanism. Ann Transl Med, 2021, 9(22): 1658.
49.	Ye Y, Chen A, Li L, et al. Repression of the antiporter SLC7A11/glutathione/glutathione peroxidase 4 axis drives ferroptosis of vascular smooth muscle cells to facilitate vascular calcification. Kidney Int, 2022, 102(6): 1259-1275.
50.	Akahori H, Tsujino T, Naito Y, et al. Intraleaflet haemorrhage as a mechanism of rapid progression of stenosis in bicuspid aortic valve. Int J Cardiol, 2013, 167(2): 514-518.
51.	Laguna-Fernandez A, Carracedo M, Jeanson G, et al. Iron alters valvular interstitial cell function and is associated with calcification in aortic stenosis. Eur Heart J, 2016, 37(47): 3532-3535.
52.	Morvan M, Arangalage D, Franck G, et al. Relationship of iron deposition to calcium deposition in human aortic valve leaflets. J Am Coll Cardiol, 2019, 73(9): 1043-1054.
53.	Xu R, Huang Y, Zhu D, et al. Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentiation: a possible mechanism by which ferroptosis participates in intraleaflet hemorrhage-induced calcification. Free Radic Biol Med, 2022, 184: 158-169.

1. Quaglino D, Boraldi F, Lofaro FD. The biology of vascular calcification. Int Rev Cell Mol Biol, 2020, 354: 261-353.
2. 董谦谦, 颜建云. 血管钙化参与细胞相关研究的新进展. 中国动脉硬化杂志, 2018, 26(11): 1111-1115.
3. Lee SJ, Lee IK, and Jeon JH. Vascular calcification-new insights into its mechanism. Int J Mol Sci, 2020, 21(8): 2685.
4. Xia J, Si H, Yao W, et al. Research progress on the mechanism of ferroptosis and its clinical application. Exp Cell Res, 2021, 409(2): 112932.
5. Li M, Wang ZW, Fang LJ, et al. Programmed cell death in atherosclerosis and vascular calcification. Cell Death Dis, 2022, 13(5): 467.
6. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
7. Xie B and Guo Y. Molecular mechanism of cell ferroptosis and research progress in regulation of ferroptosis by noncoding RNAs in tumor cells. Cell Death Discov, 2021, 7(1): 101.
8. Hu CT, Shao YD, Liu YZ, et al. Oxidative stress in vascular calcification. Clin Chim Acta, 2021, 519: 101-110.
9. 陈正东, 刘乃丰. 铁稳态在血管钙化发病机制中的作用. 中国动脉硬化杂志, 2022, 30(7): 553-559.
10. Sousa L, Oliveira MM, Pessôa MTC, et al. Iron overload: effects on cellular biochemistry. Clin Chim Acta, 2020, 504: 180-189.
11. Gammella E, Recalcati S, Rybinska I, et al. Iron-induced damage in cardiomyopathy: oxidative-dependent and independent mechanisms. Oxid Med Cell Longev, 2015, 2015: 230182.
12. Sun X, Ou Z, Xie M, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene, 2015, 34(45): 5617-5625.
13. Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol, 2017, 13(1): 91-98.
14. Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol, 2017, 13(1): 81-90.
15. Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2): 273-285.
16. Ma TL, Chen JX, Zhu P, et al. Focus on ferroptosis regulation: exploring novel mechanisms and applications of ferroptosis regulator. Life Sci, 2022, 307: 120868.
17. Fan Z, Wirth AK, Chen D, et al. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis, 2017, 6(8): e371.
18. Dodson M, Castro-Portuguez R, and Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol, 2019, 23: 101107.
19. Zhao Y, Lu J, Mao A, et al. Autophagy inhibition plays a protective role in ferroptosis induced by alcohol via the p62-Keap1-Nrf2 pathway. J Agric Food Chem, 2021, 69(33): 9671-9683.
20. He L, Liu YY, Wang K, et al. Tanshinone ⅡA protects human coronary artery endothelial cells from ferroptosis by activating the NRF2 pathway. Biochem Biophys Res Commun, 2021, 575: 1-7.
21. Liu J, Kuang F, Kroemer G, et al. Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem Biol, 2020, 27(4): 420-435.
22. Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol, 2020, 66: 89-100.
23. Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature, 2019, 575(7784): 688-692.
24. Leu JI, Murphy ME, and George DL. P53 regulates cellular redox state, ferroptosis and metabolism. Mol Cell Oncol, 2021, 8(2): 1877076.
25. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol, 2016, 26(3): 165-176.
26. Hayano M, Yang WS, Corn CK, et al. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ, 2016, 23(2): 270-278.
27. Battaglia AM, Chirillo R, Aversa I, et al. Ferroptosis and cancer: mitochondria meet the “iron maiden” cell death. Cells, 2020, 9(6): 1505.
28. Ouyang S, You J, Zhi C, et al. Ferroptosis: the potential value target in atherosclerosis. Cell Death Dis, 2021, 12(8): 782.
29. 许杰, 杨剑峰, 何杨. 铁代谢在动脉粥样硬化中的研究进展. 临床心血管病杂志, 2020, 36(6): 506-509.
30. 黄紫霞, 吴明月, 许峰, 等. 柴胡皂苷 A 通过抑制氧化应激和铁死亡减轻过氧化氢诱导的人脐静脉内皮细胞损伤. 中国动脉硬化杂志, 2022, 30(1): 43-48.
31. Marques VB, Leal MAS, Mageski JGA, et al. Chronic iron overload intensifies atherosclerosis in apolipoprotein E deficient mice: role of oxidative stress and endothelial dysfunction. Life Sci, 2019, 233: 116702.
32. Vinchi F, Porto G, Simmelbauer A, et al. Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction. Eur Heart J, 2020, 41(28): 2681-2695.
33. Bai T, Li M, Liu Y, et al. Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med, 2020, 160: 92-102.
34. Li Q, Liu C, Deng L, et al. Novel function of fluvastatin in attenuating oxidized low-density lipoprotein-induced endothelial cell ferroptosis in a glutathione peroxidase4- and cystine-glutamate antiporter-dependent manner. Exp Ther Med, 2021, 22(5): 1275.
35. 刘洋, 孙岳, 杨安宁, 等. 铁死亡参与高脂饮食诱导的 ApoE^-/-小鼠动脉粥样硬化及 ox-LDL 诱导的泡沫细胞形成过程. 实用医学杂志, 2021, 37(5): 585-590.
36. Su G, Yang W, Wang S, et al. SIRT1-autophagy axis inhibits excess iron-induced ferroptosis of foam cells and subsequently increases IL-1Beta and IL-18. Biochem Biophys Res Commun, 2021, 561: 33-39.
37. Peng Q, Liu H, Luo Z, et al. Effect of autophagy on ferroptosis in foam cells via Nrf2. Mol Cell Biochem, 2022, 477(5): 1597-1606.
38. Yang Z, Shi J, Chen L, et al. Role of pyroptosis and ferroptosis in the progression of atherosclerotic plaques. Front Cell Dev Biol, 2022, 10: 811196.
39. Al Hariri M, Zibara K, Farhat W, et al. Cigarette smoking-induced cardiac hypertrophy, vascular inflammation and injury are attenuated by antioxidant supplementation in an animal model. Front Pharmacol, 2016, 7: 397.
40. Sampilvanjil A, Karasawa T, Yamada N, et al. Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol, 2020, 318(3): H508-H518.
41. Ma WQ, Sun XJ, Zhu Y, et al. Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects. Free Radic Biol Med, 2021, 165: 229-242.
42. 黄辉. 血管钙化的基础和转化研究的探索. 中山大学学报(医学科学版), 2017, 38(2): 184-188,214.
43. Ren SC, Mao N, Yi S, et al. Vascular calcification in chronic kidney disease: an update and perspective. Aging Dis, 2022, 13(3): 673-697.
44. Seto T, Hamada C, and Tomino Y. Suppressive effects of iron overloading on vascular calcification in uremic rats. J Nephrol, 2014, 27(2): 135-142.
45. Ciceri P, Elli F, Braidotti P, et al. Iron citrate reduces high phosphate-induced vascular calcification by inhibiting apoptosis. Atherosclerosis, 2016, 254: 93-101.
46. Wang P, Guo C, Pan H, et al. Iron Sucrose: a double-edged sword in high phosphate media-induced vascular calcification. Calcif Tissue Int, 2021, 108(6): 798-807.
47. Kawada S, Nagasawa Y, Kawabe M, et al. Iron-induced calcification in human aortic vascular smooth muscle cells through interleukin-24 (IL-24), with / without TNF-alpha. Sci Rep, 2018, 8(1): 658.
48. Zhao L, Yang N, Song Y, et al. Effect of iron overload on endothelial cell calcification and its mechanism. Ann Transl Med, 2021, 9(22): 1658.
49. Ye Y, Chen A, Li L, et al. Repression of the antiporter SLC7A11/glutathione/glutathione peroxidase 4 axis drives ferroptosis of vascular smooth muscle cells to facilitate vascular calcification. Kidney Int, 2022, 102(6): 1259-1275.
50. Akahori H, Tsujino T, Naito Y, et al. Intraleaflet haemorrhage as a mechanism of rapid progression of stenosis in bicuspid aortic valve. Int J Cardiol, 2013, 167(2): 514-518.
51. Laguna-Fernandez A, Carracedo M, Jeanson G, et al. Iron alters valvular interstitial cell function and is associated with calcification in aortic stenosis. Eur Heart J, 2016, 37(47): 3532-3535.
52. Morvan M, Arangalage D, Franck G, et al. Relationship of iron deposition to calcium deposition in human aortic valve leaflets. J Am Coll Cardiol, 2019, 73(9): 1043-1054.
53. Xu R, Huang Y, Zhu D, et al. Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentiation: a possible mechanism by which ferroptosis participates in intraleaflet hemorrhage-induced calcification. Free Radic Biol Med, 2022, 184: 158-169.

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