{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:22:07Z","timestamp":1789842127156,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ondokuz May\u0131s University","award":["BAP01-2025-6131"],"award-info":[{"award-number":["BAP01-2025-6131"]}]},{"award":["BAP01-2025-6131"],"award-info":[{"award-number":["BAP01-2025-6131"]}],"id":[{"id":"https:\/\/ror.org\/028k5qw24","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Diabetic cardiomyopathy (DCM) is largely driven by severe oxidative stress and calcium dyshomeostasis. We examined the targeted antioxidant and therapeutic effects of zinc sulfate (ZnSO4) on contractile dynamics, oxidative damage, calcium turnover, and apoptosis\/fibrosis in aged female rats with type 2 diabetes. Methods: Thirty-two aged female Wistar rats were divided into Control, Control + ZnSO4, Diabetes (DM), and DM + ZnSO4 groups. DM was induced via high-fat diet and 30 mg\/kg streptozotocin. After a 4-week complication period, treatment groups received 10 mg\/kg\/day ZnSO4 (i.p.) for 6 weeks. Left ventricular papillary muscle contraction, oxidative\/antioxidant markers (MDA\/GSH), and gene expressions (SIRT1, GLUT4, SERCA2a, RyR2, Cav1.2, PLN) were evaluated. Myocardial architecture, fibrosis, and apoptosis were analyzed immunohistochemically. In DM rats, contractile force (CF) and velocities (\u00b1dF\/dtmax) significantly declined. Results: Concurrently, SIRT1, GLUT4, SERCA2a, RyR2, Cav1.2, and antioxidant GSH decreased, while oxidative lipid damage (MDA), PLN, Caspase-3 activity, Collagen I, and fibrosis increased (p &lt; 0.001). ZnSO4 treatment in diabetic rats acted as a potent antioxidant modulator; it restored redox balance, activated the SIRT1\/GLUT4 pathway, protected calcium-handling proteins from oxidative degradation, and significantly improved contractile dynamics. It also preserved myocardial architecture by reducing apoptosis and fibrosis. In healthy rats, ZnSO4 caused mild stress and early fibrosis. Conclusions: In conclusion, while inducing mild stress in healthy myocardium, zinc supplementation provides robust antioxidant protection in diabetic hearts. It activates SIRT1, suppresses oxidative damage, maintains calcium homeostasis, and restores contractile dynamics, demonstrating strong antioxidant therapeutic potential against DCM.<\/jats:p>","DOI":"10.3390\/nu18122005","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:13:37Z","timestamp":1782195217000},"page":"2005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Effect of Zinc Sulfate Treatment on Diabetic Cardiomyopathy in an Aged Female Rat Model of Type 2 Diabetes"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7750-482X","authenticated-orcid":false,"given":"Nilufer","family":"Akgun-Unal","sequence":"first","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine, Ondokuz Mayis University, 55139 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4816-830X","authenticated-orcid":false,"given":"Omer","family":"Unal","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Samsun University, 55080 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamze","family":"Altun","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine, Ondokuz Mayis University, 55139 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2391-2152","authenticated-orcid":false,"given":"Elif","family":"Gulbahce-Mutlu","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, KTO Karatay University, 42020 Konya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8269-9385","authenticated-orcid":false,"given":"Ahmet","family":"Akkoca","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine, Necmettin Erbakan University, 42090 Konya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-3080","authenticated-orcid":false,"given":"Mustafa","family":"Ayyildiz","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Ondokuz Mayis University, 55139 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(11)60679-X","article-title":"National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: Systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2\u00b77 million participants","volume":"378","author":"Danaei","year":"2011","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1152\/physrev.00045.2011","article-title":"Mechanisms of diabetic complications","volume":"93","author":"Forbes","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1161\/CIRCRESAHA.117.311586","article-title":"Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity","volume":"122","author":"Jia","year":"2018","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1161\/CIRCULATIONAHA.106.679597","article-title":"Diabetic cardiomyopathy revisited","volume":"115","author":"Boudina","year":"2007","journal-title":"Circulation"},{"key":"ref_5","first-page":"732","article-title":"Diabetic cardiomyopathy","volume":"11","author":"Acar","year":"2011","journal-title":"Anadolu Kardiyol. Derg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1002\/tox.22460","article-title":"Cellular apoptosis and cardiac dysfunction in STZ-induced diabetic rats attenuated by anthocyanins via activation of IGFI-R\/PI3K\/Akt survival signaling","volume":"32","author":"Huang","year":"2017","journal-title":"Environ. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"H1398","DOI":"10.1152\/ajpheart.00313.2002","article-title":"Defective intracellular Ca2+ signaling contributes to cardiomyopathy in Type 1 diabetic rats","volume":"283","author":"Choi","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1159\/000364779","article-title":"Effects of advanced glycation end products on calcium handling in cardiomyocytes","volume":"129","author":"Yan","year":"2014","journal-title":"Cardiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.hfc.2011.08.011","article-title":"Aging-associated cardiovascular changes and their relationship to heart failure","volume":"8","author":"Strait","year":"2012","journal-title":"Heart Fail. Clin."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kaludercic, N., and Di Lisa, F. (2020). Mitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy. Front. Cardiovasc. Med., 7.","DOI":"10.3389\/fcvm.2020.00012"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"H659","DOI":"10.1152\/ajpheart.00214.2009","article-title":"Age-associated changes in excitation-contraction coupling are more prominent in ventricular myocytes from male rats than in myocytes from female rats","volume":"298","author":"Howlett","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s00424-013-1279-z","article-title":"Sex differences in health and disease: Brain and heart connections\u2014A special issue","volume":"465","author":"Wattanapermpool","year":"2013","journal-title":"Pflug. Arch."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1161\/CIRCRESAHA.118.312498","article-title":"Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases","volume":"123","author":"Kane","year":"2018","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.ijcard.2016.11.247","article-title":"Sirtuin 1 protects the aging heart from contractile dysfunction mediated through the inhibition of endoplasmic reticulum stress-mediated apoptosis in cardiac-specific Sirtuin 1 knockout mouse model","volume":"228","author":"Hsu","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Meng, T., Qin, W., and Liu, B. (2020). SIRT1 Antagonizes Oxidative Stress in Diabetic Vascular Complication. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.568861"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S0954422412000212","article-title":"Zinc, pancreatic islet cell function and diabetes: New insights into an old story","volume":"26","author":"Chimienti","year":"2013","journal-title":"Nutr. Res. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.2174\/187153010790827957","article-title":"SIRT1, a calorie restriction mimetic, in a new therapeutic approach for type 2 diabetes mellitus and diabetic vascular complications","volume":"10","author":"Kume","year":"2010","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00204-011-0775-1","article-title":"Zinc and human health: An update","volume":"86","author":"Chasapis","year":"2012","journal-title":"Arch. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s10534-005-3689-7","article-title":"Zinc and the diabetic heart","volume":"18","author":"Song","year":"2005","journal-title":"Biometals"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Dabravolski, S.A., Sadykhov, N.K., Kartuesov, A.G., Borisov, E.E., Sukhorukov, V.N., and Orekhov, A.N. (2022). Interplay between Zn2+ Homeostasis and Mitochondrial Functions in Cardiovascular Diseases and Heart Ageing. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23136890"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1017\/S0007114517000174","article-title":"Attenuation of oxidative stress and cardioprotective effects of zinc supplementation in experimental diabetic rats","volume":"117","author":"Barman","year":"2017","journal-title":"Br. J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5235","DOI":"10.1007\/s12011-025-04550-z","article-title":"Effect of Cumulative Zinc Doses on Papillary Muscle Contractions and the Zinc Finger Protein ZEB1","volume":"203","author":"Ustun","year":"2025","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1161\/CIRCULATIONAHA.105.537894","article-title":"Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation","volume":"113","author":"Wang","year":"2006","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2902351","DOI":"10.1155\/2016\/2902351","article-title":"An Overview of Murine High Fat Diet as a Model for Type 2 Diabetes Mellitus","volume":"2016","author":"Heydemann","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"719","DOI":"10.4314\/ahs.v21i2.30","article-title":"Streptozotocin-induced type 1 and 2 diabetes in rodents: A model for studying diabetic cardiac autonomic neuropathy","volume":"21","author":"Akinlade","year":"2021","journal-title":"Afr. Health Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.phrs.2005.05.004","article-title":"Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening","volume":"52","author":"Srinivasan","year":"2005","journal-title":"Pharmacol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Li, J., Li, X., Wang, Y., Meng, L., and Cui, W. (2024). Zinc: A potential star for regulating peritoneal fibrosis. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1436864"},{"key":"ref_28","first-page":"187","article-title":"The effects of resveratrol and melatonin on cardiac dysfunction in diabetic elderly female rats","volume":"72","author":"Ozyildirim","year":"2023","journal-title":"Physiol. Res."},{"key":"ref_29","first-page":"53076","article-title":"Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice","volume":"103","author":"Uhl","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1113\/JP280899","article-title":"Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese-HFpEF","volume":"599","author":"Tickle","year":"2021","journal-title":"J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1046\/j.1365-2559.2001.01101.x","article-title":"Myocardial fibrosis assessment by semiquantitative, point-counting and computer-based methods in patients with heart muscle disease: A comparative study","volume":"38","year":"2001","journal-title":"Histopathology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"820","DOI":"10.58600\/eurjther1912","article-title":"The Effect of MitoTEMPO on Rat Diaphragm Muscle Contraction Parameters in an Experimental Diabetes Model Induced with Streptozotocin","volume":"29","author":"Ahmet","year":"2023","journal-title":"Eur. J. Ther."},{"key":"ref_34","first-page":"1942086","article-title":"Calcium Homeostasis in Ventricular Myocytes of Diabetic Cardiomyopathy","volume":"2020","year":"2020","journal-title":"J. Diabetes Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"H2164","DOI":"10.1152\/ajpheart.00428.2004","article-title":"Doxycycline inducible expression of SERCA2a improves calcium handling and reverts cardiac dysfunction in pressure overload-induced cardiac hypertrophy","volume":"287","author":"Suarez","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1093\/cvr\/cvq352","article-title":"Intracellular free zinc during cardiac excitation-contraction cycle: Calcium and redox dependencies","volume":"89","author":"Tuncay","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17599","DOI":"10.1074\/jbc.M115.661280","article-title":"Intracellular Zinc Modulates Cardiac Ryanodine Receptor-mediated Calcium Release","volume":"290","author":"Woodier","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"112043","DOI":"10.1016\/j.exger.2022.112043","article-title":"The effects of resveratrol and melatonin on biochemical and molecular parameters in diabetic old female rat hearts","volume":"172","author":"Ozyildirim","year":"2023","journal-title":"Exp. Gerontol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e1573403X1299868","DOI":"10.2174\/011573403X299868240904120621","article-title":"Importance of Zinc Homeostasis for Normal Cardiac Rhythm","volume":"21","author":"Kokhabi","year":"2025","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.jvs.2009.06.016","article-title":"Angiogenic properties of sustained release platelet-rich plasma: Characterization in-vitro and in the ischemic hind limb of the mouse","volume":"50","author":"Bir","year":"2009","journal-title":"J. Vasc. Surg."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/2005\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:22:05Z","timestamp":1782195725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/2005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,20]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["nu18122005"],"URL":"https:\/\/doi.org\/10.3390\/nu18122005","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,20]]}}}