{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:39:24Z","timestamp":1784547564275,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pomeranian Medical University in Szczecin, Poland"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chemokines are low-molecular-weight peptides classified as cytokines with chemotactic properties. The chemokine CXCL13 and its receptor CXCR5 play a significant role in cardiac remodeling, and their expression is markedly increased in experimental models of heart failure. Increased CXCL13 activity is associated with the expression of fibromodulin, a proteoglycan that binds and cross-links collagen fibers. The stressed heart undergoes intensive remodeling, including fibrosis. In our experiment, we investigated the effect of the most commonly used triple immunosuppressive regimens on the expression of the CXCR5 receptor, the chemokine CXCL13, and fibromodulin in rat heart tissue. For this purpose, we used Western blot analysis and ELISA. The study was started on 36 rats divided into 6 groups, which received drugs for a period of 6 months. Our results suggest that the chronic use of calcineurin inhibitors in combination with mycophenolate mofetil is a significant stress factor for the heart, leading to abnormal remodeling of the extracellular matrix. The use of rapamycin may alleviate the negative effects of immunosuppressive therapy on the heart. Our results are consistent with the results of our previous studies and provide a basis for further work aimed at understanding the pathophysiology of the development of changes in the heart with individual immunosuppressive regimens.<\/jats:p>","DOI":"10.3390\/ijms26136414","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T06:54:16Z","timestamp":1751525656000},"page":"6414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Chemokines and Small Leucine-Rich Proteoglycans in Cardiac Remodeling in Immunosuppressant-Treated Male Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8693-9259","authenticated-orcid":false,"given":"Anna","family":"Sur\u00f3wka","sequence":"first","affiliation":[{"name":"Department of Plastic, Endocrine and General Surgery, Pomeranian Medical University, 72-010 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4539-7342","authenticated-orcid":false,"given":"Micha\u0142","family":"\u017bo\u0142nierczuk","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, General Surgery and Angiology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Prowans","sequence":"additional","affiliation":[{"name":"Department of Plastic, Endocrine and General Surgery, Pomeranian Medical University, 72-010 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-0738","authenticated-orcid":false,"given":"Marta","family":"Grabowska","sequence":"additional","affiliation":[{"name":"Department of Histology and Developmental Biology, Faculty of Health Sciences, Pomeranian Medical University, 71-210 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0756-6483","authenticated-orcid":false,"given":"Patrycja","family":"Kupnicka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powsta\u0144c\u00f3w Wlkp. 72, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Markowska","sequence":"additional","affiliation":[{"name":"Department of Plastic, Endocrine and General Surgery, Pomeranian Medical University, 72-010 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniew","family":"Szlosser","sequence":"additional","affiliation":[{"name":"Department of Plastic, Endocrine and General Surgery, Pomeranian Medical University, 72-010 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edyta","family":"Zagrodnik","sequence":"additional","affiliation":[{"name":"Clinical Department of Anesthesiology and Intensive Care of Adults and Children, Pomeranian Medical University, 72-010 Police, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5853-2147","authenticated-orcid":false,"given":"Karolina","family":"K\u0119dzierska-Kapuza","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery and Transplantology, Centre of Postgraduate Medical Education in Warsaw, 137 Woloska St., 02-507 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dunn, S.P., and Horslen, S. (2018). Induction and Standard Immunosuppression. Solid Organ Transplantation in Infants and Children, Springer International Publishing. Organ and Tissue Transplantation.","DOI":"10.1007\/978-3-319-07284-5"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.36628\/ijhf.2020.0034","article-title":"Heart Transplant Immunosuppression Strategies at Cedars-Sinai Medical Center","volume":"3","author":"Chang","year":"2020","journal-title":"Int. J. Heart Fail."},{"key":"ref_3","first-page":"100061","article-title":"Immunosuppressive regimens following kidney transplantation in five European countries: The observational RECORD study","volume":"5","author":"Arnol","year":"2020","journal-title":"Transplant. Rep."},{"key":"ref_4","first-page":"216","article-title":"Immunosuppression after renal transplantation","volume":"12","author":"Neuwirt","year":"2019","journal-title":"Memo-Mag. Eur. Med. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sur\u00f3wka, A., \u017bo\u0142nierczuk, M., Prowans, P., Grabowska, M., Kupnicka, P., Markowska, M., Olejnik-Wojciechowska, J., Szlosser, Z., Wilk, A., and Szumilas, K. (2024). The Effects of Chronic Immunosuppressive Treatment on Morphological Changes in Cardiac Tissue and the Balance between Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitors in the Rat Heart. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084468"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sur\u00f3wka, A., Szumilas, K., Wilk, A., Misiakiewicz-Has, K., Ciechanowski, K., and K\u0119dzierska-Kapuza, K. (2022). The Effect of Chronic Immunosuppressive Regimens Treatment on Aortal Media Morphology and the Balance between Matrix Metalloproteinases (mmp-2 and mmp-9) and Their Inhibitors in the Abdominal Aorta of Rats. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19116399"},{"key":"ref_7","first-page":"726","article-title":"Immunosuppressive Drugs","volume":"4","author":"Hussain","year":"2022","journal-title":"Encycl. Infect. Immun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a015669","DOI":"10.1101\/cshperspect.a015669","article-title":"Opportunistic Infections\u2014Coming to the Limits of Immunosuppression?","volume":"3","author":"Fishman","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1080\/08923973.2021.1966033","article-title":"Transplantation and immunosuppression: A review of novel transplant-related immunosuppressant drugs","volume":"43","author":"Parlakpinar","year":"2021","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Elezaby, A., Dexheimer, R., and Sallam, K. (2022). Cardiovascular effects of immunosuppression agents. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.981838"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sur\u00f3wka, A., Prowans, P., \u017bo\u0142nierczuk, M., Mi\u015bkiewicz, M., Wawrowski, T., Skodda, M., Markowska, M., and K\u0119dzierska-Kapuza, K. (2023). The Effect of Calcineurin Inhibitors on MMPs Activity in Heart and Their Side Effects\u2014A Review of Literature. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210291"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e26019","DOI":"10.1097\/MD.0000000000026019","article-title":"Cardiovascular mortality in liver and kidney transplant recipients","volume":"100","author":"Knotek","year":"2021","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1093\/eurjhf\/hfp029","article-title":"Understanding the \u2018epidemic of heart failure\u2019: A systematic review of trends in determinants of heart failure","volume":"11","author":"Najafi","year":"2009","journal-title":"Eur. J. Heart Fail."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"ii2","DOI":"10.1136\/heart.89.suppl_2.ii2","article-title":"Global risk of cardiovascular disease","volume":"89","author":"Poulter","year":"2003","journal-title":"Heart"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.tibs.2004.09.002","article-title":"The biochemical response of the heart to hypertension and exercise","volume":"29","author":"Wakatsuki","year":"2004","journal-title":"Trends Biochem. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","article-title":"Mechanisms of physiological and pathological cardiac hypertrophy","volume":"15","author":"Nakamura","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0735-1097(99)00630-0","article-title":"Cardiac remodeling--concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling","volume":"35","author":"Cohn","year":"2000","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.yjmcc.2008.05.025","article-title":"Cardiac stem cells and myocardial disease","volume":"45","author":"Kajstura","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1152\/physrev.00012.2007","article-title":"Myocardial matrix remodeling and the matrix metalloproteinases: Influence on cardiac form and function","volume":"87","author":"Spinale","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jacc.2006.01.077","article-title":"Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure","volume":"48","author":"Querejeta","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4065","DOI":"10.1161\/01.CIR.96.11.4065","article-title":"Extracellular matrix remodeling in heart failure: A role for de novo angiotensin II generation","volume":"96","author":"Weber","year":"1997","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Patrichi, G., Patrichi, A., Satala, C.-B., and Sin, A.I. (2023). Matrix Metalloproteinases and Heart Transplantation\u2014A Pathophysiological and Clinical View. Medicina, 59.","DOI":"10.3390\/medicina59071295"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sur\u00f3wka, A., \u017bo\u0142nierczuk, M., Prowans, P., Grabowska, M., Kupnicka, P., Markowska, M., Szlosser, Z., and K\u0119dzierska-Kapuza, K. (2024). The Effect of Chronic Immunosuppressive Regimen Treatment on Apoptosis in the Heart of Rats. Pharmaceuticals, 17.","DOI":"10.3390\/ph17091188"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"156261","DOI":"10.1016\/j.cyto.2023.156261","article-title":"Cytokines and their role in cardiovascular diseases","volume":"169","author":"Haybar","year":"2023","journal-title":"Cytokine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0008-6363(99)00381-8","article-title":"Chemokines and cardiovascular diseases","volume":"45","author":"Sasayama","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_26","first-page":"861","article-title":"i R.J. Markery procesu zapalnego a niewydolno\u015b\u0107 serca","volume":"11","author":"Gil","year":"2004","journal-title":"Cardiol. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.dci.2003.09.006","article-title":"Chemokines","volume":"28","author":"Laing","year":"2004","journal-title":"Dev. Comp. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S1074-7613(00)80165-X","article-title":"Chemokines: A New Classification System and Their Role in Immunity","volume":"12","author":"Zlotnik","year":"2000","journal-title":"Immunity"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Gao, S.-H., Liu, S.-Z., Wang, G.-Z., and Zhou, G.-B. (2021). CXCL13 in Cancer and Other Diseases: Biological Functions, Clinical Significance, and Therapeutic Opportunities. Life, 11.","DOI":"10.3390\/life11121282"},{"key":"ref_30","first-page":"S801","article-title":"Abstract 3395: The Homeostatic Chemokine CXCL13 and Its Receptor CXCR5 Are Regulated in Heart Failure and Are Involved in Cardiac Remodelling","volume":"120","author":"Waehre","year":"2009","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Waehre, A., Halvorsen, B., Yndestad, A., Husberg, C., Sjaastad, I., Nyg\u00e5rd, S., Dahl, C.P., Ahmed, M.S., Finsen, A.V., and Reims, H. (2011). Lack of chemokine signaling through CXCR5 causes increased mortality, ventricular dilatation and deranged matrix during cardiac pressure overload. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018668"},{"key":"ref_32","unstructured":"W\u00e6hre, A. (2025, March 18). Chemokines in Cardiac Remodelling and Heart Failure, and Their Role in Regulation of Small Leucinerich Proteoglycans in The Extracellular Matrix. Available online: https:\/\/www.semanticscholar.org\/paper\/Chemokines-in-cardiac-remodelling-and-heart-and-in-W%C3%A6hre\/b8683be296d50af5b8cce3457c516237f2258f0a."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5902947","DOI":"10.1155\/2016\/5902947","article-title":"Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems","volume":"2016","author":"Dusi","year":"2016","journal-title":"Mediators Inflamm."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zhao, F., Bai, Y., Xiang, X., and Pang, X. (2023). The role of fibromodulin in inflammatory responses and diseases associated with inflammation. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1191787"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"18873","DOI":"10.1074\/jbc.M114.572941","article-title":"Increased C-telopeptide cross-linking of tendon type I collagen in fibromodulin-deficient mice","volume":"289","author":"Kalamajski","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7951","DOI":"10.1074\/jbc.M115.693408","article-title":"Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase","volume":"291","author":"Kalamajski","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e831","DOI":"10.1002\/ctm2.831","article-title":"Targeting inflammation with collagen","volume":"12","author":"Schwarz","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Opa\u0142ka, B., \u017bo\u0142nierczuk, M., and Grabowska, M. (2023). Immunosuppressive Agents\u2014Effects on the Cardiovascular System and Selected Metabolic Aspects: A Review. J. Clin. Med., 12.","DOI":"10.3390\/jcm12216935"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1007\/s00228-010-0902-6","article-title":"Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: Systematic review with meta-analyses and trial sequential analyses of randomised trials","volume":"66","author":"Penninga","year":"2010","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1097\/00007890-200005150-00039","article-title":"Tacrolimus and myocardial hypertrophy","volume":"69","author":"Nakata","year":"2000","journal-title":"Transplantation"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Zeng, J., Zhong, Q., Feng, X., Li, L., Feng, S., Fan, Y., Song, T., Huang, Z., Wang, X., and Lin, T. (2021). Conversion From Calcineurin Inhibitors to Mammalian Target of Rapamycin Inhibitors in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.663602"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1161\/01.HYP.0000257914.80918.72","article-title":"FK506 Binding Protein 12\/12.6 Depletion Increases Endothelial Nitric Oxide Synthase Threonine 495 Phosphorylation and Blood Pressure","volume":"49","author":"Long","year":"2007","journal-title":"Hypertension"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:03:48Z","timestamp":1760033028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,3]]},"references-count":42,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136414"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136414","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,3]]}}}