{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:07:16Z","timestamp":1791522436124,"version":"4.3.4"},"reference-count":50,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["IP-2019-04-1449"],"award-info":[{"award-number":["IP-2019-04-1449"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 ageHTx\/LVAD, 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.<\/jats:p>","DOI":"10.3390\/ijms25179648","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T03:22:46Z","timestamp":1725592966000},"page":"9648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cardiotoxicity of Iron and Zinc and Their Association with the Mitochondrial Unfolded Protein Response in Humans"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1966-4731","authenticated-orcid":false,"given":"Vid","family":"Mirosevic","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-1239","authenticated-orcid":false,"given":"Tomo","family":"Svagusa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, Dubrava University Hospital, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3299-4241","authenticated-orcid":false,"given":"Natalija","family":"Matic","sequence":"additional","affiliation":[{"name":"Department of Development and Water Management, Croatian Waters, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kresimir","family":"Maldini","sequence":"additional","affiliation":[{"name":"Josip Juraj Stossmayer Water Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Siljeg","sequence":"additional","affiliation":[{"name":"Josip Juraj Stossmayer Water Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davor","family":"Milicic","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Cardiovascular Diseases, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hrvoje","family":"Gasparovic","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Cardiac Surgery, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7735-6721","authenticated-orcid":false,"given":"Igor","family":"Rudez","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Department of Cardiac and Transplant Surgery, Dubrava University Hospital, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Sepac","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"},{"name":"Ljudevit Jurak Department of Pathology, Sestre Milosrdnice University Hospital Centre, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucija","family":"Gojmerac","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0176-1886","authenticated-orcid":false,"given":"Ana","family":"Kulic","sequence":"additional","affiliation":[{"name":"Department of Oncology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Bakovic","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Sedlic","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169374","DOI":"10.1016\/j.scitotenv.2023.169374","article-title":"Molybdenum Exposure Induces Inflammatory Response via the Regulatory Effects of lncRNA-00072124\/miR-308\/OSMR Crosstalk on JAK\/STAT Axis in Duck Kidneys","volume":"912","author":"Pu","year":"2024","journal-title":"Sci. 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