Unveiling Cadmium-Induced Cardiotoxicity: Mechanisms, Challenges, and Future Perspectives: A Narrative Review
-
Mandana Pouladzadeh
,
Masoud Danjeh
,
Negin Yousefi Chermehini
,
Somayeh Zamanifard
,
Ali Abesi
,
Parisa Molaee
,
Hadi Rezaeeyan
Abstract
We investigated the mechanisms of cadmium-induced cardiotoxicity, focusing on its pathophysiological effects, potential preventive strategies, and therapeutic interventions. We further explored approaches to mitigate long-term cardiovascular risks associated with cadmium exposure. This research analyzed the molecular and cellular pathways involved in cadmium toxicity, emphasizing oxidative stress, inflammation, endothelial dysfunction, platelet-leukocyte interactions, and cardiomyocyte damage. Experimental findings and existing literature were examined to uncover the mechanisms driving cadmium-induced cardiotoxicity and to identify potential therapeutic targets. Cadmium exposure leads to oxidative stress and inflammation, resulting in endothelial dysfunction, platelet-leukocyte activation, and thromboinflammation. It disrupts calcium signaling, elevates reactive oxygen species (ROS) production, and causes cardiomyocyte loss, ultimately impairing cardiac function. Cadmium also remodels ion channels and suppresses cardiomyocyte proliferation, intensifying its cardiotoxic effects. While current therapies focus on removing circulating cadmium, they do not address the residual cardiovascular damage caused by prior exposure. Cadmium exerts significant cardiotoxic effects through oxidative stress, inflammation, and cellular activation. Future therapeutic strategies should target these pathways, particularly the activation of platelets, leukocytes, and endothelial cells, to reduce cadmium-induced cardiovascular damage and improve long-term outcomes.
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2. Wei S, Ma W, Li X, Jiang C, et al (2020). Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin-Induced Cardiotoxicity. Cardiovasc Toxicol, 20(5):507-519.
3. Rafati Rahimzadeh M, Rafati Rahimzadeh M, Kazemi S, et al (2017). Cadmium toxicity and treatment: An update. Caspian J Intern Med, 8 (3):135-145.
4. Lin H-C, Hao W-M, Chu P-H (2021). Cadmium and cardiovascular disease: An overview of pathophysiology, epidemiology, therapy, and predictive value. Rev Port Cardiol (Engl Ed), 40 (8):611-617.
5. Genchi G, Sinicropi MS, Lauria G, et al (2020). The Effects of Cadmium Toxicity. Int J Environ Res Public Health, 17(11):3782.
6. Zhao L, Liao M, Li L, et al (2024). Cadmium activates the innate immune system through the AIM2 inflammasome. Chem Biol Interact, 399:111122.
7. Thompson J, Bannigan J (2008). Cadmium: toxic effects on the reproductive system and the embryo. Reprod Toxicol, 25 (3):304-15.
8. Weshahy AR, Sakr AK, Gouda AA, et al (2022). Selective Recovery of Cadmium, Cobalt, and Nickel from Spent Ni-Cd Batteries Using Adogen(®) 464 and Mesoporous Silica Derivatives. Int J Mol Sci, 23(15):8677.
9. Abdrabou D, Ahmed M, Hussein A, El-Sherbini T (2023). Photocatalytic behavior for removal of methylene blue from aqueous solutions via nanocomposites based on Gd(2)O(3)/CdS and cellulose acetate nanofibers. Environ Sci Pollut Res Int, 30 (44):99789-99808.
10. Li L, Wang J, Xu S, Li C, Dong B (2022). Recent Progress in Fluorescent Probes For Metal Ion Detection. Front Chem, 10:875241.
11. Hadi IH, Khashan KS, Sulaiman D (2021). Cadmium sulphide (CdS) nanoparticles: Preparation and characterization. Materials Today: Proceedings, 42:3054-3056.
12. Azizi M, Ghourchian H, Yazdian F, Alizadehzeinabad H (2018). Albumin coated cadmium nanoparticles as chemotherapeutic agent against MDA-MB 231 human breast cancer cell line. Artif Cells Nanomed Biotechnol, 46 (sup1):787-797.
13. Chen CY, Zhang SL, Liu ZY, Tian Y, Sun Q (2015). Cadmium toxicity induces ER stress and apoptosis via impairing energy homoeostasis in cardiomyocytes. Biosci Rep, 35(3):e00214.
14. Liu M, Chen R, Zheng Z, et al (2025). Mechanisms of inflammatory microenvironment formation in cardiometabolic diseases: molecular and cellular perspectives. Front Cardiovasc Med, 11:1529903.
15. Barregard L, Sallsten G, Harari F, et al (2021). Cadmium Exposure and Coronary Artery Atherosclerosis: A Cross-Sectional Population-Based Study of Swedish Middle-Aged Adults. Environ Health Perspect, 129 (6):67007.
16. Tinkov AA, Filippini T, Ajsuvakova OP, et al (2018). Cadmium and atherosclerosis: A review of toxicological mechanisms and a meta-analysis of epidemiologic studies. Environ Res, 162:240-260.
17. Yao Y, Zhao X, Zheng S, et al (2021). Subacute cadmium exposure promotes M1 macrophage polarization through oxidative stress-evoked inflammatory response and induces porcine adrenal fibrosis. Toxicology, 461:152899.
18. Zhang Y, Zhu L, Li X, et al (2024). M2 macrophage exosome-derived lncRNA AK083884 protects mice from CVB3-induced viral myocarditis through regulating PKM2/HIF-1α axis mediated metabolic reprogramming of macrophages. Redox Biol, 69:103016.
19. Aksu K, Donmez A, Keser G (2012). Inflammation-induced thrombosis: mechanisms, disease associations and management. Curr Pharm Des, 18 (11):1478-93.
20. Cai J, Guan H, Jiao X, et al (2021). NLRP3 inflammasome mediated pyroptosis is involved in cadmium exposure-induced neuroinflammation through the IL-1β/IkB-α-NF-κB-NLRP3 feedback loop in swine. Toxicology, 453:152720.
21. Xi H, Zhang Y, Xu Y, et al (2016). Caspase-1 Inflammasome Activation Mediates Homocysteine-Induced Pyrop-Apoptosis in Endothelial Cells. Circ Res, 118 (10):1525-39.
22. Zheng Y, Xu L, Dong N, Li F (2022). NLRP3 inflammasome: The rising star in cardiovascular diseases. Front Cardiovasc Med, 9:927061.
23. Pouladzadeh M, Safdarian M, Choghakabodi PM, et al (2021). Validation of red cell distribution width as a COVID-19 severity screening tool. Future Sci OA, 7(7):FSO712.
24. Sahu R, Dua TK, Das S, et al (2019). Wheat phenolics suppress doxorubicin-induced cardiotoxicity via inhibition of oxidative stress, MAP kinase activation, NF-κB pathway, PI3K/Akt/mTOR impairment, and cardiac apoptosis. Food Chem Toxicol, 125:503-519.
25. Das SC, Varadharajan K, Shanmugakonar M, Al-Naemi HA (2021). Chronic Cadmium Exposure Alters Cardiac Matrix Metalloproteinases in the Heart of Sprague-Dawley Rat. Front Pharmacol, 12:663048.
26. Giannandrea M, Parks WC (2014). Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech, 7 (2):193-203.
27. Bormann T, Maus R, Stolper J, et al (2022). Role of matrix metalloprotease-2 and MMP-9 in experimental lung fibrosis in mice. Respir Res, 23(1):180.
28. Heyno E, Klose C, Krieger-Liszkay A (2008). Origin of cadmium-induced reactive oxygen species production: mitochondrial electron transfer versus plasma membrane NADPH oxidase. New Phytol, 179 (3):687-699.
29. Sinenko SA, Starkova TY, Kuzmin AA, et al (2021). Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man. Front Cell Dev Biol, 9:714370.
30. Bhattacharyya A, Chattopadhyay R, Mitra S, et al (2014). Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev, 94 (2):329-54.
31. Fujii J, Homma T, Osaki T (2022). Superoxide Radicals in the Execution of Cell Death. Antioxidants (Basel), 11(3):501.
32. Kang MA, So EY, Simons AL, et al (2012). DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway. Cell Death Dis, 3(1):e249.
33. Zhao RZ, Jiang S, Zhang L, Yu ZB (2019). Mitochondrial electron transport chain, ROS generation and uncoupling (Review). Int J Mol Med, 44 (1):3-15.
34. Persad KL, Lopaschuk GD (2022). Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate. Front Cell Dev Biol, 10:886393.
35. Morgan MJ, Liu Z-g (2011). Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res, 21 (1):103-115.
36. Zang H, Mathew RO, Cui T (2020). The Dark Side of Nrf2 in the Heart. Front Physiol, 11:722.
37. Görlach A, Bertram K, Hudecova S, Krizanova O (2015). Calcium and ROS: A mutual interplay. Redox Biol, 6:260-271.
38. Prakriya M (2020). Calcium and cell function. J Physiol, 598 (9):1647-1648.
39. Behringer EJ (2017). Calcium and electrical signaling in arterial endothelial tubes: New insights into cellular physiology and cardiovascular function. Microcirculation, 24(3):10.1111/micc.12328.
40. Dewenter M, von der Lieth A, Katus HA, et al (2017). Calcium Signaling and Transcriptional Regulation in Cardiomyocytes. Circ Res, 121 (8):1000-1020.
41. Hohendanner F, McCulloch AD, Blatter LA, et al (2014). Calcium and IP3 dynamics in cardiac myocytes: experimental and computational perspectives and approaches. Front Pharmacol, 5:35.
42. Vassalle M, Lin C-I (2004). Calcium overload and cardiac function. J Biomed Sci, 11 (5):542-565.
43. Li WQ, Tan SL, Li XH, et al (2019). Calcitonin gene-related peptide inhibits the cardiac fibroblasts senescence in cardiac fibrosis via up-regulating klotho expression. Eur J Pharmacol, 843:96-103.
44. Choong G, Liu Y, Templeton DM (2014). Interplay of calcium and cadmium in mediating cadmium toxicity. Chem Biol Interact, 211:54-65.
45. Verbost PM, Flik G, Lock RA, et al (1988). Cadmium inhibits plasma membrane calcium transport. J Membr Biol, 102 (2):97-104.
46. Li K, Guo C, Ruan J, et al (2023). Cadmium Disrupted ER Ca(2+) Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells. Int J Mol Sci, 24(6):5979.
47. Lawal AO, Ellis EM (2012). Phospholipase C Mediates Cadmium-Dependent Apoptosis in HEK 293 Cells. Basic Clin Pharmacol Toxicol, 110(6):510-7.
48. Liu J, Yu L, Castro L, et al (2019). A nongenomic mechanism for "metalloestrogenic" effects of cadmium in human uterine leiomyoma cells through G protein-coupled estrogen receptor. Arch Toxicol, 93 (10):2773-2785.
49. Ahumada-Castro U, Bustos G, Silva-Pavez E, et al (2021). In the Right Place at the Right Time: Regulation of Cell Metabolism by IP3R-Mediated Inter-Organelle Ca2+ Fluxes. Front Cell Dev Biol, 9:629522.
50. Zhou X, Hao W, Shi H, Hou Y, Xu Q (2015). Calcium homeostasis disruption - a bridge connecting cadmium-induced apoptosis, autophagy and tumorigenesis. Oncol Res Treat, 38 (6):311-5.
51. Shimada BK, Yorichika N, Higa JK, et al (2021). mTOR-mediated calcium transients affect cardiac function in ex vivo ischemia-reperfusion injury. Physiol Rep, 9 (6):e14807.
52. Branca JJV, Pacini A, Gulisano M, et al (2020). Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain. Front Cell Dev Biol, 8:604377.
53. Padula SL, Velayutham N, Yutzey KE (2021). Transcriptional Regulation of Postnatal Cardiomyocyte Maturation and Regeneration. Int J Mol Sci, 22 (6): 3288.
54. Choghakabodi PM, Pouladzadeh M, Haybar H, et al (2020). Biological whistleblowers for silent myocardial ischemia: diagnostic and prognostic approach [Informatori biologici per ischemia miocardica silente: approccio diagnostico e prognostico.]. Recenti Prog Med, 111(7):415-425.
55. Johnson J, Mohsin S, Houser SR (2021). Cardiomyocyte Proliferation as a Source of New Myocyte Development in the Adult Heart. Int J Mol Sci, 22 (15):7764.
56. Cao N, Huang Y, Zheng J, et al (2016). Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science, 352 (6290):1216-1220.
57. Ahmad W, Saleh B, Qazi R-e-M, et al (2024). Direct differentiation of rat skin fibroblasts into cardiomyocytes. Exp Cell Res, 435 (2):113934.
58. Lin Z, Zhou P, von Gise A, et al (2015). Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ Res, 116(1):35-45.
59. Luo J-S, Zhang Z (2021). Mechanisms of cadmium phytoremediation and detoxification in plants. The Crop Journal, 9 (3):521-529.
60. Stietiya MH, Wang JJ (2014). Zinc and Cadmium Adsorption to Aluminum Oxide Nanoparticles Affected by Naturally Occurring Ligands. J Environ Qual, 43 (2):498-506.
61. Klaassen CD, Waalkes MP, Cantilena LR, Jr. (1984). Alteration of tissue disposition of cadmium by chelating agents. Environ Health Perspect, 54:233-42.
62. Dosoky WM, Farag SA, Almuraee AA, et al (2024). Vitamin C and/or garlic can antagonize the toxic effects of cadmium on growth performance, hematological, and immunological parameters of growing Japanese quail. Poult Sci, 103 (3):103457.
63. Ansari MN, Ganaie MA, Rehman NU, et al (2019). Protective role of Roflumilast against cadmium-induced cardiotoxicity through inhibition of oxidative stress and NF-κB signaling in rats. Saudi Pharm J, 27 (5):673-681.
64. Williams CR, Harrison RM (1984). Cadmium in the atmosphere. Experientia, 40 (1):29-36.
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| Files | ||
| Issue | Vol 54 No 8 (2025) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v54i8.19576 | |
| Keywords | ||
| Cadmium Cardiotoxicity Heavy metal exposure Pathogenesis Thrombosis Thromboinflammation | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Pouladzadeh M, Danjeh M, Yousefi Chermehini N, Zamanifard S, Abesi A, Molaee P, Rezaeeyan H. Unveiling Cadmium-Induced Cardiotoxicity: Mechanisms, Challenges, and Future Perspectives: A Narrative Review. Iran J Public Health. 2025;54(8):1678-1688.
