Is Ferroptosis and Oxidative Stress Involved in NSTEMI Patient’s?
-
Ali Mirzaei
,
Maryam Mehrpooya
,
Akram Ranjbar
,
Sajad Naghdi
,
Afsaneh Familmotaghi
,
Seyed Saman Talebi
,
Seyed Kianoosh Hosseini
Abstract
Background: Ischemic heart disease is the leading cause of death worldwide. Oxidative stress plays a key role in myocardial infarction (MI). Ferroptosis, a type of iron-dependent regulated cell death caused by lipid peroxide accumulation, has been identified as a key mechanism in ischemic injury. This study aimed to investigate the association between oxidative stress and ferroptosis in patients with non–ST-segment-elevation myocardial infarction (NSTEMI).
Methods: In this case-control study, 25 patients with NSTEMI and 25 controls were included. In serum samples, cardiac markers (troponin I and CK-MB), oxidative stress biomarkers including lipid peroxidation (LPO), total antioxidant capacity (TAC), total thiol groups (TTG), superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, and iron and ferritin levels were measured.
Results: In patients with NSTEMI, serum levels of cardiac markers (troponin I and CK-MB), LPO, iron, and ferritin were significantly higher than in controls. In contrast, TAC, TTG, and SOD and GPx activities were significantly lower in patients with NSTEMI.
Conclusion: This study demonstrated a possible role of oxidative stress in the pathophysiology of NSTEMI. Elevated iron and LPO levels and reduced GPx activity may contribute to cardiac cell death through ferroptosis.
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3. Sies H, Berndt C, Jones DP. Oxidative stress. Annual review of biochemistry. 2017;86(1):715-48.
4. Bolli R, Jeroudi MO, Patel BS, Aruoma OI, Halliwell B, Lai EK, et al. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial" stunning" is a manifestation of reperfusion injury. Circulation Research. 1989;65(3):607-22.
5. Heusch G. Myocardial ischaemia–reperfusion injury and cardioprotection in perspective. Nature Reviews Cardiology. 2020;17(12):773-89.
6. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death & Differentiation. 2018;25(3):486-541.
7. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. cell. 2012;149(5):1060-72.
8. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends in cell biology. 2016;26(3):165-76.
9. Ahsan H, Hasan MY, Ahmad R. Ferroptosis: Oxidative stress and pathophysiology. Novel Therapeutic Approaches Targeting Oxidative Stress: Elsevier; 2022. p. 19-26.
10. Kroemer G, Tang D. Ferroptosis: Springer; 2023.
11. Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. Journal of hematology & oncology. 2019;12:1-16.
12. Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochemical and biophysical research communications. 2017;482(3):419-25.
13. Zhao Y, Pan B, Lv X, Chen C, Li K, Wang Y, et al. Ferroptosis: roles and molecular mechanisms in diabetic cardiomyopathy. Frontiers in Endocrinology. 2023;14:1140644.
14. Wu X, Li Y, Zhang S, Zhou X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics. 2021;11(7):3052.
15. Saxena P, Selvaraj K, Khare SK, Chaudhary N. Superoxide dismutase as multipotent therapeutic antioxidant enzyme: Role in human diseases. Biotechnology letters. 2022:1-22.
16. Marwicka J, Zięba A. Antioxidants as a defence against reactive oxygen species. Aesthetic Cosmetol Med. 2021;10:271-6.
17. Gusti AM, Qusti SY, Alshammari EM, Toraih EA, Fawzy MS. Antioxidants-related superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (GST), and nitric oxide synthase (NOS) gene variants analysis in an obese population: a preliminary case-control study. Antioxidants. 2021;10(4):595.
18. He F, Zuo L. Redox roles of reactive oxygen species in cardiovascular diseases. International journal of molecular sciences. 2015;16(11):27770-80.
19. Dubois-Deruy E, Peugnet V, Turkieh A, Pinet F. Oxidative stress in cardiovascular diseases. Antioxidants. 2020;9(9):864.
20. Xie Y, Kang R, Klionsky DJ, Tang D. GPX4 in cell death, autophagy, and disease. Autophagy. 2023;19(10):2621-38.
21. Tossounian M-A, Zhao Y, Yu BYK, Markey SA, Malanchuk O, Zhu Y, et al. Low-molecular-weight thiol transferases in redox regulation and antioxidant defence. Redox Biology. 2024:103094.
22. Averill-Bates DA. The antioxidant glutathione. Vitamins and hormones. 121: Elsevier; 2023. p. 109-41.
23. Noctor G, Cohen M, Trémulot L, Châtel-Innocenti G, Van Breusegem F, Mhamdi A. Glutathione: a key modulator of plant defence and metabolism through multiple mechanisms. Journal of Experimental Botany. 2024;75(15):4549-72.
24. Andreadou I, Efentakis P, Frenis K, Daiber A, Schulz R. Thiol-based redox-active proteins as cardioprotective therapeutic agents in cardiovascular diseases. Basic research in cardiology. 2021;116(1):44.
25. Kundi H, Ates I, Kiziltunc E, Cetin M, Cicekcioglu H, Neselioglu S, et al. A novel oxidative stress marker in acute myocardial infarction; thiol/disulphide homeostasis. The American journal of emergency medicine. 2015;33(11):1567-71.
26. Kasap S, Gönenç A, Şener DE, Hisar İ. Serum cardiac markers in patients with acute myocardial infarction: oxidative stress, C-reactive protein and N-terminal probrain natriuretic peptide. Journal of clinical biochemistry and nutrition. 2007;41(1):50-7.
27. El-Mahdy RI, Mostafa MM, El-Deen HS. Serum zinc measurement, total antioxidant capacity, and lipid peroxide among acute coronary syndrome patients with and without ST elevation. Applied biochemistry and biotechnology. 2019;188:208-24.
28. Babu S, Shetty JK, Mungli P. Total thiols and MDA levels in patients with acute myocardial infarction before and after reperfusion therapy. Online Journal of Health and Allied Sciences. 2010;9(3).
29. Aladağ N, Asoğlu R, Ozdemir M, Asoğlu E, Derin AR, Demir C, et al. Oxidants and antioxidants in myocardial infarction (MI): Investigation of ischemia modified albumin, malondialdehyde, superoxide dismutase and catalase in individuals diagnosed with ST elevated myocardial infarction (STEMI) and non-STEMI (NSTEMI). Journal of Medical Biochemistry. 2021;40(3):286.
30. Khan HA, Alhomida AS, Sobki SH, Habib SS, Al Aseri Z, Khan AA, et al. Serum markers of tissue damage and oxidative stress in patients with acute myocardial infarction. Biomed Res. 2013;24(1):15-20.
31. Kurniawan PR, Setiawan AA, Limantoro C, Ariosta A. the Differences in Troponin I and Ck-Mb Values in Acute Myocardial Infarction Patients With St Elevation and Without St Elevation. Jurnal Kedokteran Diponegoro (Diponegoro Medical Journal). 2021;10(2):138-44.
32. Yamashita T, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Hatori M, et al. Creatinine kinase-myocardial band (CK-MB) to creatinine kinase (CK) ratio for ST-segment elevation myocardial infarction in the era of the universal definition. Heart and Vessels. 2024;39(11):988-90.
33. Muranov KO. Fenton Reaction in vivo and in vitro. Possibilities and Limitations. Biochemistry (Moscow). 2024;89(Suppl 1):S112-S26.
34. Zhao Z. Hydroxyl radical generations form the physiologically relevant Fenton-like reactions. Free Radical Biology and Medicine. 2023;208:510-5.
35. Ying J-F, Lu Z-B, Fu L-Q, Tong Y, Wang Z, Li W-F, et al. The role of iron homeostasis and iron-mediated ROS in cancer. American journal of cancer research. 2021;11(5):1895.
36. Galaris D, Barbouti A, Pantopoulos K. Iron homeostasis and oxidative stress: An intimate relationship. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2019;1866(12):118535.
37. Chaulin AM. The importance of cardiac troponin metabolism in the laboratory diagnosis of myocardial infarction (Comprehensive Review). BioMed Research International. 2022;2022(1):6454467.
38. Wang C, Zhou Z, Zhou H, Xiang K, Tang W, Wu X, et al. NCOA4 promotes myocardial injury by upregulating ferroptosis in long-term smoking mice. Journal of the Renin-Angiotensin-Aldosterone System. 2025;26:14703203251401455.
39. Millett ER, Peters SA, Woodward M. Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants. bmj. 2018;363.
40. Sagris M, Antonopoulos AS, Theofilis P, Oikonomou E, Siasos G, Tsalamandris S, et al. Risk factors profile of young and older patients with myocardial infarction. Cardiovascular research. 2022;118(10):2281-92.
41. Kanuri B, Biswas P, Dahdah A, Murphy AJ, Nagareddy PR. Impact of age and sex on myelopoiesis and inflammation during myocardial infarction. Journal of Molecular and Cellular Cardiology. 2024;187:80-9.
42. Mehta RH, Rathore SS, Radford MJ, Wang Y, Wang Y, Krumholz HM. Acute myocardial infarction in the elderly: differences by age. Journal of the American College of Cardiology. 2001;38(3):736-41.
43. Ru Q, Li Y, Xie W, Ding Y, Chen L, Xu G, et al. Fighting age-related orthopedic diseases: focusing on ferroptosis. Bone research. 2023;11(1):12.
2. Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox biology. 2015;6:524-51.
3. Sies H, Berndt C, Jones DP. Oxidative stress. Annual review of biochemistry. 2017;86(1):715-48.
4. Bolli R, Jeroudi MO, Patel BS, Aruoma OI, Halliwell B, Lai EK, et al. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial" stunning" is a manifestation of reperfusion injury. Circulation Research. 1989;65(3):607-22.
5. Heusch G. Myocardial ischaemia–reperfusion injury and cardioprotection in perspective. Nature Reviews Cardiology. 2020;17(12):773-89.
6. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death & Differentiation. 2018;25(3):486-541.
7. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. cell. 2012;149(5):1060-72.
8. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends in cell biology. 2016;26(3):165-76.
9. Ahsan H, Hasan MY, Ahmad R. Ferroptosis: Oxidative stress and pathophysiology. Novel Therapeutic Approaches Targeting Oxidative Stress: Elsevier; 2022. p. 19-26.
10. Kroemer G, Tang D. Ferroptosis: Springer; 2023.
11. Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. Journal of hematology & oncology. 2019;12:1-16.
12. Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochemical and biophysical research communications. 2017;482(3):419-25.
13. Zhao Y, Pan B, Lv X, Chen C, Li K, Wang Y, et al. Ferroptosis: roles and molecular mechanisms in diabetic cardiomyopathy. Frontiers in Endocrinology. 2023;14:1140644.
14. Wu X, Li Y, Zhang S, Zhou X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics. 2021;11(7):3052.
15. Saxena P, Selvaraj K, Khare SK, Chaudhary N. Superoxide dismutase as multipotent therapeutic antioxidant enzyme: Role in human diseases. Biotechnology letters. 2022:1-22.
16. Marwicka J, Zięba A. Antioxidants as a defence against reactive oxygen species. Aesthetic Cosmetol Med. 2021;10:271-6.
17. Gusti AM, Qusti SY, Alshammari EM, Toraih EA, Fawzy MS. Antioxidants-related superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (GST), and nitric oxide synthase (NOS) gene variants analysis in an obese population: a preliminary case-control study. Antioxidants. 2021;10(4):595.
18. He F, Zuo L. Redox roles of reactive oxygen species in cardiovascular diseases. International journal of molecular sciences. 2015;16(11):27770-80.
19. Dubois-Deruy E, Peugnet V, Turkieh A, Pinet F. Oxidative stress in cardiovascular diseases. Antioxidants. 2020;9(9):864.
20. Xie Y, Kang R, Klionsky DJ, Tang D. GPX4 in cell death, autophagy, and disease. Autophagy. 2023;19(10):2621-38.
21. Tossounian M-A, Zhao Y, Yu BYK, Markey SA, Malanchuk O, Zhu Y, et al. Low-molecular-weight thiol transferases in redox regulation and antioxidant defence. Redox Biology. 2024:103094.
22. Averill-Bates DA. The antioxidant glutathione. Vitamins and hormones. 121: Elsevier; 2023. p. 109-41.
23. Noctor G, Cohen M, Trémulot L, Châtel-Innocenti G, Van Breusegem F, Mhamdi A. Glutathione: a key modulator of plant defence and metabolism through multiple mechanisms. Journal of Experimental Botany. 2024;75(15):4549-72.
24. Andreadou I, Efentakis P, Frenis K, Daiber A, Schulz R. Thiol-based redox-active proteins as cardioprotective therapeutic agents in cardiovascular diseases. Basic research in cardiology. 2021;116(1):44.
25. Kundi H, Ates I, Kiziltunc E, Cetin M, Cicekcioglu H, Neselioglu S, et al. A novel oxidative stress marker in acute myocardial infarction; thiol/disulphide homeostasis. The American journal of emergency medicine. 2015;33(11):1567-71.
26. Kasap S, Gönenç A, Şener DE, Hisar İ. Serum cardiac markers in patients with acute myocardial infarction: oxidative stress, C-reactive protein and N-terminal probrain natriuretic peptide. Journal of clinical biochemistry and nutrition. 2007;41(1):50-7.
27. El-Mahdy RI, Mostafa MM, El-Deen HS. Serum zinc measurement, total antioxidant capacity, and lipid peroxide among acute coronary syndrome patients with and without ST elevation. Applied biochemistry and biotechnology. 2019;188:208-24.
28. Babu S, Shetty JK, Mungli P. Total thiols and MDA levels in patients with acute myocardial infarction before and after reperfusion therapy. Online Journal of Health and Allied Sciences. 2010;9(3).
29. Aladağ N, Asoğlu R, Ozdemir M, Asoğlu E, Derin AR, Demir C, et al. Oxidants and antioxidants in myocardial infarction (MI): Investigation of ischemia modified albumin, malondialdehyde, superoxide dismutase and catalase in individuals diagnosed with ST elevated myocardial infarction (STEMI) and non-STEMI (NSTEMI). Journal of Medical Biochemistry. 2021;40(3):286.
30. Khan HA, Alhomida AS, Sobki SH, Habib SS, Al Aseri Z, Khan AA, et al. Serum markers of tissue damage and oxidative stress in patients with acute myocardial infarction. Biomed Res. 2013;24(1):15-20.
31. Kurniawan PR, Setiawan AA, Limantoro C, Ariosta A. the Differences in Troponin I and Ck-Mb Values in Acute Myocardial Infarction Patients With St Elevation and Without St Elevation. Jurnal Kedokteran Diponegoro (Diponegoro Medical Journal). 2021;10(2):138-44.
32. Yamashita T, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Hatori M, et al. Creatinine kinase-myocardial band (CK-MB) to creatinine kinase (CK) ratio for ST-segment elevation myocardial infarction in the era of the universal definition. Heart and Vessels. 2024;39(11):988-90.
33. Muranov KO. Fenton Reaction in vivo and in vitro. Possibilities and Limitations. Biochemistry (Moscow). 2024;89(Suppl 1):S112-S26.
34. Zhao Z. Hydroxyl radical generations form the physiologically relevant Fenton-like reactions. Free Radical Biology and Medicine. 2023;208:510-5.
35. Ying J-F, Lu Z-B, Fu L-Q, Tong Y, Wang Z, Li W-F, et al. The role of iron homeostasis and iron-mediated ROS in cancer. American journal of cancer research. 2021;11(5):1895.
36. Galaris D, Barbouti A, Pantopoulos K. Iron homeostasis and oxidative stress: An intimate relationship. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2019;1866(12):118535.
37. Chaulin AM. The importance of cardiac troponin metabolism in the laboratory diagnosis of myocardial infarction (Comprehensive Review). BioMed Research International. 2022;2022(1):6454467.
38. Wang C, Zhou Z, Zhou H, Xiang K, Tang W, Wu X, et al. NCOA4 promotes myocardial injury by upregulating ferroptosis in long-term smoking mice. Journal of the Renin-Angiotensin-Aldosterone System. 2025;26:14703203251401455.
39. Millett ER, Peters SA, Woodward M. Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants. bmj. 2018;363.
40. Sagris M, Antonopoulos AS, Theofilis P, Oikonomou E, Siasos G, Tsalamandris S, et al. Risk factors profile of young and older patients with myocardial infarction. Cardiovascular research. 2022;118(10):2281-92.
41. Kanuri B, Biswas P, Dahdah A, Murphy AJ, Nagareddy PR. Impact of age and sex on myelopoiesis and inflammation during myocardial infarction. Journal of Molecular and Cellular Cardiology. 2024;187:80-9.
42. Mehta RH, Rathore SS, Radford MJ, Wang Y, Wang Y, Krumholz HM. Acute myocardial infarction in the elderly: differences by age. Journal of the American College of Cardiology. 2001;38(3):736-41.
43. Ru Q, Li Y, Xie W, Ding Y, Chen L, Xu G, et al. Fighting age-related orthopedic diseases: focusing on ferroptosis. Bone research. 2023;11(1):12.
| Files | ||
| Issue | Vol 21 No 1 (2026) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/jthc.v21i1.21281 | |
| Keywords | ||
| Non–ST-Segment Elevation Myocardial Infarction Oxidative Stress Stress; Ferroptosis | ||
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How to Cite
1.
Mirzaei A, Mehrpooya M, Ranjbar A, Naghdi S, Familmotaghi A, Talebi SS, Hosseini SK. Is Ferroptosis and Oxidative Stress Involved in NSTEMI Patient’s?. Res Heart Yield Transl Med. 2026;21(1):32-39.
