Cardiotoxicity of Iron and Zinc and Their Association with the Mitochondrial Unfolded Protein Response in Humans

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Sep 14

PMID 39273594

Authors

Vid Mirosevic

Tomo Svagusa

Natalija Matic

Kresimir Maldini

Mario Siljeg

Davor Milicic

Hrvoje Gasparovic

Igor Rudez

Ana Sepac

Lucija Gojmerac

Ana Kulic

Petra Bakovic

Filip Sedlic

Affiliations

Soon will be listed here.

Abstract

This study was designed to examine the association between myocardial concentrations of the trace elements Cu, Fe, Mn, Mo, and Zn and the expression of mitochondrial unfolded protein response (UPRmt) elements and the age of patients who received heart transplantation or a left-ventricular assist device (ageHTx/LVAD). Inductively coupled plasma mass spectrometry was used to determine the concentration of Cu, Fe, Mn, Mo, and Zn in the myocardium of control subjects and patients undergoing heart transplantation or left-ventricular assist device (LVAD) implantation. We used ELISA to quantify the expression of UPRmt proteins and 4-Hydroxynonenal (4-HNE), which served as a marker of oxidative-stress-induced lipid peroxidation. Concentrations of Cu, Mn, Mo, and Zn were similar in the control and heart failure (HF) myocardium, while Fe showed a significant decrease in the HF group compared to the control. A higher cumulative concentration of Fe and Zn in the myocardium was associated with reduced age, which was not observed for other combinations of trace elements or their individual effects. The trace elements Cu, Mn, and Zn showed positive correlations with several UPRmt proteins, while Fe had a negative correlation with UPRmt effector protease YME1L. None of the trace elements correlated with 4-HNE in the myocardium. The concentrations of the trace elements Mn and Zn were significantly higher in the myocardium of patients with dilated cardiomyopathy than in patients with ischemic cardiomyopathy. A higher cumulative concentration of Fe and Zn in the myocardium was associated with a younger age at which patients received heart transplantation or LVAD, potentially suggesting an acceleration of HF. A positive correlation between myocardial Cu, Mn, and Zn and the expression of UPRmt proteins and a negative correlation between myocardial Fe and YME1L expression suggest that these trace elements exerted their actions on the human heart by interacting with the UPRmt. An altered generation of oxidative stress was not an underlying mechanism of the observed changes.

References

Smyrnias I, Gray S, Okonko D, Sawyer G, Zoccarato A, Catibog N . Cardioprotective Effect of the Mitochondrial Unfolded Protein Response During Chronic Pressure Overload. J Am Coll Cardiol. 2019; 73(14):1795-1806. PMC: 6456800. DOI: 10.1016/j.jacc.2018.12.087. View

Horn D, Barrientos A . Mitochondrial copper metabolism and delivery to cytochrome c oxidase. IUBMB Life. 2008; 60(7):421-9. PMC: 2864105. DOI: 10.1002/iub.50. View

Ripa S, Ripa R . [Zinc and arterial pressure]. Minerva Med. 1994; 85(9):455-9. View

Joshi P, Patel S, Shreya D, Zamora D, Patel G, Grossmann I . Hereditary Hemochromatosis: A Cardiac Perspective. Cureus. 2022; 13(11):e20009. PMC: 8716004. DOI: 10.7759/cureus.20009. View

Suliburska J, Skrypnik K, Szulinska M, Kupsz J, Markuszewski L, Bogdanski P . Diuretics, Ca-Antagonists, and Angiotensin-Converting Enzyme Inhibitors Affect Zinc Status in Hypertensive Patients on Monotherapy: A Randomized Trial. Nutrients. 2018; 10(9). PMC: 6164079. DOI: 10.3390/nu10091284. View

Sepac A, Sedlic F, Si-Tayeb K, Lough J, Duncan S, Bienengraeber M . Isoflurane preconditioning elicits competent endogenous mechanisms of protection from oxidative stress in cardiomyocytes derived from human embryonic stem cells. Anesthesiology. 2010; 113(4):906-16. PMC: 2945423. DOI: 10.1097/ALN.0b013e3181eff6b7. View

Yan F, Li K, Xing W, Dong M, Yi M, Zhang H . Role of Iron-Related Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Diseases. Oxid Med Cell Longev. 2022; 2022:5124553. PMC: 9473912. DOI: 10.1155/2022/5124553. View

Kamalov G, Holewinski J, Bhattacharya S, Ahokas R, Sun Y, Gerling I . Nutrient dyshomeostasis in congestive heart failure. Am J Med Sci. 2009; 338(1):28-33. DOI: 10.1097/MAJ.0b013e3181aaee63. View

Wai T, Garcia-Prieto J, Baker M, Merkwirth C, Benit P, Rustin P . Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science. 2016; 350(6265):aad0116. DOI: 10.1126/science.aad0116. View

10.

Sepac A, Si-Tayeb K, Sedlic F, Barrett S, Canfield S, Duncan S . Comparison of cardiomyogenic potential among human ESC and iPSC lines. Cell Transplant. 2012; 21(11):2523-30. PMC: 3522765. DOI: 10.3727/096368912X653165. View

11.

Wu X, Chen Y, Luz A, Hu G, Tokar E . Cardiac Development in the Presence of Cadmium: An Study Using Human Embryonic Stem Cells and Cardiac Organoids. Environ Health Perspect. 2022; 130(11):117002. PMC: 9628677. DOI: 10.1289/EHP11208. View

12.

Choi S, Liu X, Pan Z . Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases. Acta Pharmacol Sin. 2018; 39(7):1120-1132. PMC: 6289396. DOI: 10.1038/aps.2018.25. View

13.

Ahmed S, Peterson S, Parikh M, Frishman W . Cardiovascular Manifestations of Hemochromatosis: A Review of Pathophysiology, Mechanisms, and Treatment Options. Cardiol Rev. 2023; . DOI: 10.1097/CRD.0000000000000622. View

14.

Wang M, Tian Y, Yu P, Li N, Deng Y, Li L . Association between congenital heart defects and maternal manganese and iron concentrations: a case-control study in China. Environ Sci Pollut Res Int. 2021; 29(18):26950-26959. PMC: 8989826. DOI: 10.1007/s11356-021-17054-9. View

15.

Piavchenko G, Alekseev A, Stelmashchuk O, Seryogina E, Zherebtsov E, Kuznetsova E . A complex morphofunctional approach for zinc toxicity evaluation in rats. Heliyon. 2020; 6(4):e03768. PMC: 7177034. DOI: 10.1016/j.heliyon.2020.e03768. View

16.

Touati D . Iron and oxidative stress in bacteria. Arch Biochem Biophys. 2000; 373(1):1-6. DOI: 10.1006/abbi.1999.1518. View

17.

Harding D, Chong M, Lahoti N, Bigogno C, Prema R, Mohiddin S . Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy. J Intern Med. 2022; 293(1):23-47. DOI: 10.1111/joim.13556. View

18.

Kerins M, Ooi A . The Roles of NRF2 in Modulating Cellular Iron Homeostasis. Antioxid Redox Signal. 2017; 29(17):1756-1773. PMC: 6208163. DOI: 10.1089/ars.2017.7176. View

19.

Svagusa T, Martinic M, Martinic M, Kovacevic L, Sepac A, Milicic D . Mitochondrial unfolded protein response, mitophagy and other mitochondrial quality control mechanisms in heart disease and aged heart. Croat Med J. 2020; 61(2):126-138. PMC: 7230417. View

20.

Pravdic D, Sedlic F, Mio Y, Vladic N, Bienengraeber M, Bosnjak Z . Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein Kinase C-epsilon-mediated pathway. Anesthesiology. 2009; 111(2):267-74. PMC: 2744603. DOI: 10.1097/ALN.0b013e3181a91957. View