{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:01:43Z","timestamp":1790812903477,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UWM Statutory","award":["61.610.007-110"],"award-info":[{"award-number":["61.610.007-110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Copper (Cu), being an essential mineral, plays a crucial role in maintaining physiological homeostasis across multiple bodily systems, notably the cardiovascular system. However, an increased Cu level in the body may cause blood vessel dysfunction and oxidative stress, which is unfavorable for the cardiovascular system. Middle-aged (7\u20138 months old) male Wistar rats (n\/group = 12) received a diet supplemented with 6.45 mg Cu\/kg (100% of the recommended daily dietary quantity of copper) for 8 weeks (Group A). The experimental group received 12.9 mg Cu\/kg of diet (200%\u2014Group B). An ex vivo study revealed that supplementation with 200% Cu decreased the contraction of isolated aortic rings to noradrenaline (0.7-fold) through FP receptor modulation. Vasodilation to sodium nitroprusside (1.10-fold) and acetylcholine (1.13-fold) was potentiated due to the increased net effect of prostacyclin derived from cyclooxygenase-1. Nitric oxide (NO, 2.08-fold), superoxide anion (O2\u2022\u2212, 1.5-fold), and hydrogen peroxide (H2O2, 2.33-fold) measured in the aortic rings increased. Blood serum antioxidant status (TAS, 1.6-fold), Cu (1.2-fold), Zn (1.1-fold), and the Cu\/Zn ratio (1.4-fold) increased. An increase in Cu (1.12-fold) and the Cu\/Zn ratio (1.09-fold) was also seen in the rats\u2019 livers. Meanwhile, cyclooxygenase-1 (0.7-fold), cyclooxygenase-2 (0.4-fold) and glyceraldehyde 3-phosphate dehydrogenase (0.5-fold) decreased. Moreover, a negative correlation between Cu and Zn was found (r = \u22120.80) in rat serum. Supplementation with 200% Cu did not modify the isolated heart functioning. No significant difference was found in the body weight, fat\/lean body ratio, and organ weight for either the heart or liver, spleen, kidney, and brain. Neither Fe nor Se, the Cu\/Se ratio, the Se\/Zn ratio (in serum and liver), heme oxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), or intercellular adhesion molecule-1 (iCAM-1) (in serum) were modified. Supplementation with 200% of Cu potentiated pro-oxidant status and modified vascular contractility in middle-aged rats.<\/jats:p>","DOI":"10.3390\/nu16081172","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T08:08:12Z","timestamp":1713168492000},"page":"1172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Effect of an Elevated Dietary Copper Level on the Vascular Contractility and Oxidative Stress in Middle-Aged Rats"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3566-2853","authenticated-orcid":false,"given":"Klaudia","family":"Kitala-Ta\u0144ska","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5949-7061","authenticated-orcid":false,"given":"Katarzyna","family":"Socha","sequence":"additional","affiliation":[{"name":"Department of Bromatology, Medical University of Bia\u0142ystok, 15-222 Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0068-5970","authenticated-orcid":false,"given":"Jerzy","family":"Ju\u015bkiewicz","sequence":"additional","affiliation":[{"name":"Division of Food Science, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7857-347X","authenticated-orcid":false,"given":"Magdalena","family":"Krajewska-W\u0142odarczyk","sequence":"additional","affiliation":[{"name":"Department of Mental and Psychosomatic Diseases, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6304-0673","authenticated-orcid":false,"given":"Micha\u0142","family":"Majewski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Erdman, J.W., Macdonald, I.A., and Zeisel, S.H. (2012). Present Knowledge in Nutrition, Wiley\u2212Blackwell. [10th ed.].","DOI":"10.1002\/9781119946045"},{"key":"ref_2","unstructured":"Ross, A.C., Caballero, B., Cousins, R.J., Tucker, K.L., and Ziegler, T.R. (2014). Modern Nutrition in Health and Disease, Lippincott Williams & Wilkins. [11th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1152\/ajpcell.00132.2018","article-title":"Copper transporters and copper chaperones: Roles in cardiovascular physiology and disease","volume":"315","author":"Fukai","year":"2018","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.tox.2011.03.001","article-title":"Advances in metal\u2212induced oxidative stress and human disease","volume":"283","author":"Jomova","year":"2011","journal-title":"Toxicology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"k3310","DOI":"10.1136\/bmj.k3310","article-title":"Environmental toxic metal contaminants and risk of cardiovascular disease: Systematic review and meta\u2212analysis","volume":"362","author":"Chowdhury","year":"2018","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.2527\/jas.2011-4403","article-title":"Amount and source of dietary copper affects small intestine morphology, duodenal lipid peroxidation, hepatic oxidative stress, and mRNA expression of hepatic copper regulatory proteins in weanling pigs","volume":"90","author":"Fry","year":"2012","journal-title":"J. Anim. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.pharmthera.2010.11.004","article-title":"Copper and homocysteine in cardiovascular diseases","volume":"129","author":"Kang","year":"2011","journal-title":"Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0009-9120(03)00059-6","article-title":"Plasma homocysteine levels in obese and non\u2212obese subjects with or without hypertension; its relationship with oxidative stress and copper","volume":"36","author":"Serin","year":"2003","journal-title":"Clin. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1080\/15287394.2018.1437490","article-title":"Acute copper overload induces vascular dysfunction in aortic rings due to endothelial oxidative stress and increased nitric oxide production","volume":"81","author":"Nunes","year":"2018","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7092151","DOI":"10.1155\/2019\/7092151","article-title":"Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease","volume":"2019","author":"Steven","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1161\/HYPERTENSIONAHA.117.07802","article-title":"Oxidative Stress, Inflammation, and Vascular Aging in Hypertension","volume":"70","author":"Guzik","year":"2017","journal-title":"Hypertension"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1016\/j.metabol.2012.02.002","article-title":"A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular health","volume":"61","author":"DiSilvestro","year":"2012","journal-title":"Metabolism"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Majewski, M., Gromadzi\u0144ski, L., Cholewi\u0144ska, E., Ognik, K., Fotschki, B., and Ju\u015bkiewicz, J. (2023). The Interaction of Dietary Pectin, Inulin, and Psyllium with Copper Nanoparticle Induced Changes to the Cardiovascular System. Nutrients, 15.","DOI":"10.3390\/nu15163557"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.pharep.2019.02.007","article-title":"Copper nanoparticles modify the blood plasma antioxidant status and modulate the vascular mechanisms with nitric oxide and prostanoids involved in Wistar rats","volume":"71","author":"Majewski","year":"2019","journal-title":"Pharmacol. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.pharep.2019.03.011","article-title":"The interaction between resveratrol and two forms of copper as carbonate and nanoparticles on antioxidant mechanisms and vascular function in Wistar rats","volume":"71","author":"Majewski","year":"2019","journal-title":"Pharmacol. Rep."},{"key":"ref_16","unstructured":"National Research Council (US) Subcommittee on Laboratory Animal Nutrition (2024, April 14). 2, Nutrient Requirements of the Laboratory Rat, Nutrient Requirements of Laboratory Animals, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK231925."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"103595","DOI":"10.1016\/j.jff.2019.103595","article-title":"The antioxidant status, lipid profile, and modulation of vascular function by fish oil supplementation in nano-copper and copper carbonate fed Wistar rats","volume":"64","author":"Majewski","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1080\/13880209.2022.2047209","article-title":"Spirulina extract improves age-induced vascular dysfunction","volume":"60","author":"Majewski","year":"2022","journal-title":"Pharm. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1385\/BTER:82:1-3:159","article-title":"Effects of micromolar concentrations of manganese, copper, and zinc on alpha1\u2212adrenoceptor\u2212mediating contraction in rat aorta","volume":"82","author":"Yan","year":"2001","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1159\/000354523","article-title":"Copper induces vasorelaxation and antagonizes noradrenaline\u2212induced vasoconstriction in rat mesenteric artery","volume":"32","author":"Wang","year":"2013","journal-title":"Cell Physiol. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Afrin, F., Basir, S.F., and Khan, L.A. (2022). Copper\u2212promoted hypercontraction of rat aortic rings and its mitigation by natural molecules, Preprint.","DOI":"10.21203\/rs.3.rs-2005722\/v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/aps.2010.111","article-title":"Inhibition of iNOS protects endothelial\u2212dependent vasodilation in aged rats","volume":"31","author":"Tian","year":"2010","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1113\/jphysiol.2004.080952","article-title":"Mechanisms of acetylcholine\u2212mediated vasodilatation in young and aged human skin","volume":"563","author":"Holowatz","year":"2005","journal-title":"J. Physiol"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/j.0959-9673.2005.00432.x","article-title":"Dietary copper supplements modulate aortic superoxide dismutase, nitric oxide and atherosclerosis","volume":"86","author":"Lamb","year":"2005","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1038\/sj.bjp.0704816","article-title":"Effect of prolonged incubation with copper on endothelium\u2212dependent relaxation in rat isolated aorta","volume":"136","author":"Chiarugi","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/sj.bjp.0702374","article-title":"Investigation of the inhibitory effects of homocysteine and copper on nitric oxide\u2212mediated relaxation of rat isolated aorta","volume":"126","author":"Emsley","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1093\/jn\/122.11.2101","article-title":"Copper\u2212marginal and copper\u2212deficient diets decrease aortic prostacyclin production and copper\u2212dependent superoxide dismutase activity, and increase aortic lipid peroxidation in rats","volume":"122","author":"Nelson","year":"1992","journal-title":"J. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Majewski, M., Ju\u015bkiewicz, J., Krajewska\u2212W\u0142odarczyk, M., Gromadzi\u0144ski, L., Socha, K., Cholewi\u0144ska, E., and Ognik, K. (2021). The Role of 20\u2212HETE, COX, Thromboxane Receptors, and Blood Plasma Antioxidant Status in Vascular Relaxation of Copper\u2212Nanoparticle\u2212Fed WKY Rats. Nutrients, 13.","DOI":"10.3390\/nu13113793"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107624","DOI":"10.1016\/j.pharmthera.2020.107624","article-title":"Cyclooxygenases and the cardiovascular system","volume":"217","author":"Mitchell","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s10753-009-9140-4","article-title":"Cyclooxygenase\u22122 is upregulated in copper\u2212deficient rats","volume":"32","author":"Schuschke","year":"2009","journal-title":"Inflammation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1111\/j.1440-1681.2011.05599.x","article-title":"GAPDH: A common enzyme with uncommon functions","volume":"39","author":"Nicholls","year":"2012","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1111\/cts.12053","article-title":"Real\u2212time RT\u2212PCR Ct values for blood GAPDH correlate with measures of vascular endothelial function in humans","volume":"6","author":"Khan","year":"2013","journal-title":"Clin. Transl. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1136\/jcp.54.5.339","article-title":"Measurement of total antioxidant capacity","volume":"54","author":"Young","year":"2001","journal-title":"J. Clin. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1093\/jn\/138.2.305","article-title":"Associations of dietary and serum copper with inflammation, oxidative stress, and metabolic variables in adults","volume":"138","author":"Bo","year":"2008","journal-title":"J. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"0495","DOI":"10.4172\/2161-0495.S3-001","article-title":"Copper and zinc, biological role and significance of copper\/zinc imbalance","volume":"S3","author":"Osredkar","year":"2011","journal-title":"J. Clinic Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/S0749-0690(02)00040-X","article-title":"Trace metals and the elderly","volume":"18","author":"McClain","year":"2002","journal-title":"Clin. Geriatr. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"49","DOI":"10.51791\/njap.v22i1.2028","article-title":"Copper and iron supplementation in the tropical environment effects on haematological measurements, organ weights, tissue copper and iron","volume":"22","author":"Agunbiade","year":"1995","journal-title":"Niger. J. Anim. Prod."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s12012-023-09797-3","article-title":"Cardiovascular Harmful Effects of Recommended Daily Doses (13 \u00b5g\/kg\/day), Tolerable Upper Intake Doses (0.14 mg\/kg\/day) and Twice the Tolerable Doses (0.28 mg\/kg\/day) of Copper","volume":"23","author":"Filetti","year":"2023","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Banach, W., Nitschke, K., Krajewska, N., Mongia\u0142\u0142o, W., Matuszak, O., Muszy\u0144ski, J., and Skrypnik, D. (2020). The Association between Excess Body Mass and Disturbances in Somatic Mineral Levels. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197306"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1093\/jn\/116.7.1248","article-title":"Lipid and Fatty Acid Composition of Organs from Copper\u2212Deficient Mice","volume":"116","author":"Cunnane","year":"1986","journal-title":"J. Nutr."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/8\/1172\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:28:04Z","timestamp":1760106484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/8\/1172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,15]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["nu16081172"],"URL":"https:\/\/doi.org\/10.3390\/nu16081172","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,15]]}}}