{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:16:08Z","timestamp":1791832568995,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetes is a major risk factor for the development of cardiovascular disease with a higher incidence of myocardial infarction. This study explores the role of metformin, a first-line antihyperglycemic agent, in postinfarction fibrotic and inflammatory remodeling in mice. Three-month-old C57BI\/6J mice were submitted to 30 min cardiac ischemia followed by reperfusion for 14 days. Intraperitoneal treatment with metformin (5 mg\/kg) was initiated 15 min after the onset of reperfusion and maintained for 14 days. Real-time PCR was used to determine the levels of COL3A1, \u03b1SMA, CD68, TNF-\u03b1 and IL-6. Increased collagen deposition and infiltration of macrophages in heart tissues are associated with upregulation of the inflammation-associated genes in mice after 14 days of reperfusion. Metformin treatment markedly reduced postinfarction fibrotic remodeling and CD68-positive cell population in mice. Moreover, metformin resulted in reduced expression of COL3A1, \u03b1SMA and CD68 after 14 days of reperfusion. Taken together, these results open new perspectives for the use of metformin as a drug that counteracts adverse myocardial fibroticand inflammatory remodeling after MI.<\/jats:p>","DOI":"10.3390\/ijms22179393","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T11:01:37Z","timestamp":1630321297000},"page":"9393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Metformin Attenuates Postinfarction Myocardial Fibrosis and Inflammation in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Halyna","family":"Loi","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmcology, I. Horbachevsky Ternopil National Medical University, 46009 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solomiia","family":"Kramar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmcology, I. Horbachevsky Ternopil National Medical University, 46009 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Laborde","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-5514","authenticated-orcid":false,"given":"Dimitri","family":"Marsal","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Pizzinat","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7227-898X","authenticated-orcid":false,"given":"Daniel","family":"Cussac","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Roncalli","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7607-4573","authenticated-orcid":false,"given":"Frederic","family":"Boal","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6117-8054","authenticated-orcid":false,"given":"Helene","family":"Tronchere","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleksandra","family":"Oleshchuk","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmcology, I. Horbachevsky Ternopil National Medical University, 46009 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mykhaylo","family":"Korda","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmcology, I. Horbachevsky Ternopil National Medical University, 46009 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Kunduzova","sequence":"additional","affiliation":[{"name":"National Institute of Health and Medical Research (INSERM) U1297, CEDEX 4, 31432 Toulouse, France"},{"name":"University of Toulouse III, CEDEX 9, 31062 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1056\/NEJM199807233390404","article-title":"Mortality from Coronary Heart Disease in Subjects with Type 2 Diabetes and in Nondiabetic Subjects with and without Prior Myocardial Infarction","volume":"339","author":"Haffner","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jchf.2014.08.004","article-title":"Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure","volume":"3","author":"Khan","year":"2015","journal-title":"JACC Hear Fail."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/S0008-6363(97)00018-7","article-title":"The diabetic heart is more sensitive to ischemic injury","volume":"34","author":"Paulson","year":"1997","journal-title":"Cardiovasc. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12933-015-0299-8","article-title":"SIRT1 protects against myocardial ischemia\u2013reperfusion injury via activating eNOS in diabetic rats","volume":"14","author":"Ding","year":"2015","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1177\/1089253211436350","article-title":"Myocardial ischemia reperfusion injury\u2014From basic science to clinical bedside","volume":"16","author":"Frank","year":"2012","journal-title":"Semin. Cardiothorac. Vasc. Anesth."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.pharmthera.2011.11.004","article-title":"The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion","volume":"33","author":"Raedschelders","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0735-1097(99)00630-0","article-title":"Cardiac remodeling\u2014Concepts and clinical implications: A consensus paper from an international forum on cardiac remodeling","volume":"35","author":"Cohn","year":"2000","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1161\/CIRCHEARTFAILURE.110.960039","article-title":"The Adverse Impact of Diabetes Mellitus on Left Ventricular Remodeling and Function in Patients with Severe Aortic Stenosis","volume":"4","author":"Lindman","year":"2011","journal-title":"Circ. Heart Fail."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrcardio.2011.154","article-title":"Cardiac remodeling at the population level\u2014risk factors, screening, and outcomes","volume":"8","author":"Gjesdal","year":"2011","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1136\/hrt.2004.046540","article-title":"Effects of eplerenone on transcriptional factors and mRNA expression related to cardiac remodelling after myocardial infarction","volume":"91","author":"Enomoto","year":"2005","journal-title":"Heart"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrcardio.2014.28","article-title":"The inflammatory response in myocardial injury, repair, and remodelling","volume":"11","author":"Frangogiannis","year":"2014","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ijcard.2008.04.059","article-title":"Macrophage roles following myocardial infarction","volume":"130","author":"Lambert","year":"2008","journal-title":"Int. J. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/labinvest.2016.116","article-title":"CD68\/macrosialin: Not just a histochemical marker","volume":"97","author":"Chistiakov","year":"2016","journal-title":"Lab. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1161\/01.RES.0000130526.20854.fa","article-title":"Inflammatory Cytokines and Postmyocardial Infarction Remodeling","volume":"94","author":"Nian","year":"2004","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Eguchi, M., Kim, Y.H., Kang, K.W., Shim, C.Y., Jang, Y., Dorval, T., Kim, K.J., and Sweeney, G. (2012). Ischemia-Reperfusion Injury Leads to Distinct Temporal Cardiac Remodeling in Normal versus Diabetic Mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030450"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s10741-010-9169-3","article-title":"Cellular and molecular pathways to myocardial necrosis and replacement fibrosis","volume":"16","author":"Gandhi","year":"2010","journal-title":"Heart Fail. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1160\/TH08-12-0837","article-title":"The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury","volume":"102","author":"Steffens","year":"2009","journal-title":"Thromb. Haemost."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s00441-016-2431-9","article-title":"Cardiac fibrosis in myocardial infarction\u2014from repair and remodeling to regeneration","volume":"365","author":"Talman","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.yjmcc.2013.11.015","article-title":"Fibroblasts in myocardial infarction: A role in inflammation and repair","volume":"70","author":"Shinde","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1093\/eurheartj\/ehr389","article-title":"Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1","volume":"33","author":"Pchejetski","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16864","DOI":"10.1073\/pnas.0607700103","article-title":"Fibrosis, not cell size, delineates \u03b2-myosin heavy chain reexpression during cardiac hyperthrophy and normal aging in vivo","volume":"103","author":"Pandya","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"merican Diabetes Association (2020). Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care, 43, S98\u2013S110.","DOI":"10.2337\/dc20-S009"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1056\/NEJMoa0806470","article-title":"10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes","volume":"359","author":"Holman","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1046\/j.1365-2125.1999.00092.x","article-title":"The UK Prospective Diabetes Study (UKPDS): Clinical and therapeutic implications for type 2 diabetes","volume":"48","author":"King","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1111\/j.1464-5491.2010.03098.x","article-title":"Metformin action on AMP-activated protein kinase: A translational research approach to understanding a potential new therapeutic target","volume":"27","author":"Boyle","year":"2010","journal-title":"Diabet Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.7326\/0003-4819-137-1-200207020-00009","article-title":"Metformin: An Update","volume":"137","author":"Kirpichnikov","year":"2002","journal-title":"Ann. Intern. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12265-012-9410-7","article-title":"Communication in the Heart: The Role of the Innate Immune System in Coordinating Cellular Responses to Ischemic Injury","volume":"5","author":"Epelman","year":"2012","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fphar.2019.00154","article-title":"Metformin protects the heart against hypertrophic and apoptotic remodeling after myocardial infarction","volume":"10","author":"Loi","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/nrcardio.2012.158","article-title":"Myofibroblast-mediated mechanisms of pathological remodelling of the heart","volume":"10","author":"Weber","year":"2012","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrcardio.2009.199","article-title":"Myocardial remodeling after infarction: The role of myofibroblasts","volume":"7","author":"Borne","year":"2009","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1093\/cvr\/cvq066","article-title":"Metformin attenuates cardiac fibrosis by inhibiting the TGF1-Smad3 signalling pathway","volume":"87","author":"Xiao","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, X., Yang, L., Kang, L., Li, J., Yang, L., Zhang, J., Liu, J., Zhu, M., Zhang, Q., and Shen, Y. (2017). Metformin attenuates myocardial ischemia-reperfusion injury via up-regulation of antioxidant enzymes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182777"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.yjmcc.2010.10.033","article-title":"Transforming Growth Factor (TGF)-\u03b2 signaling in cardiac remodeling Introduction: The biology of TGF-\u03b2","volume":"51","author":"Dobaczewski","year":"2011","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1161\/CIRCRESAHA.108.190918","article-title":"Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure","volume":"104","author":"Gundewar","year":"2009","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.numecd.2017.04.009","article-title":"Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data","volume":"27","author":"Nesti","year":"2017","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1172\/JCI74783","article-title":"Resident fibroblast lineages mediate pressure overload\u2013induced cardiac fibrosis","volume":"124","author":"Banerjee","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1056\/NEJMra1300575","article-title":"Fibrosis\u2014A Common Pathway to Organ Injury and Failure","volume":"372","author":"Rockey","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12260","DOI":"10.1038\/ncomms12260","article-title":"Genetic lineage tracing defines myofibroblast origin and function in the injured heart","volume":"7","author":"Kanisicak","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41584-019-0324-5","article-title":"Evasion of apoptosis by myofibroblasts: A hallmark of fibrotic diseases","volume":"16","author":"Hinz","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1161\/CIRCULATIONAHA.119.042375","article-title":"Effect of Empagliflozin on Left Ventricular Mass in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial","volume":"140","author":"Verma","year":"2019","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1177\/1479164114562411","article-title":"Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes","volume":"12","author":"Koska","year":"2015","journal-title":"Diabetes Vasc. Dis. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101866","DOI":"10.1016\/j.redox.2021.101866","article-title":"Galanin promotes autophagy and alleviates apoptosis in the hypertrophied heart through FoxO1 pathway","volume":"40","author":"Martinelli","year":"2021","journal-title":"Redox Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.yjmcc.2019.12.001","article-title":"In vitro and in vivo cardioprotective and metabolic efficacy of vitamin E TPGS\/Apelin","volume":"138","author":"Goto","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_45","first-page":"2448","article-title":"Wheat germ agglutinin staining as a suitable method for detection and quantification of fibrosis in cardiac tissue after myocardial infarction","volume":"58","author":"Emde","year":"2014","journal-title":"Eur. J. Histochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/ijo.2014.122","article-title":"Transition from metabolic adaptation to maladaptation of the heart in obesity: Role of apelin","volume":"39","author":"Alfarano","year":"2014","journal-title":"Int. J. Obes."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9393\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:55:39Z","timestamp":1760165739000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,30]]},"references-count":46,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22179393"],"URL":"https:\/\/doi.org\/10.3390\/ijms22179393","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,30]]}}}