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This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone\u2013TLR interactions and their mechanisms.<\/jats:p>","DOI":"10.3390\/ijms25168653","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T15:04:24Z","timestamp":1723129464000},"page":"8653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Impact of Extracellular Histones and Absence of Toll-like Receptors on Cardiac Functional and Electrical Disturbances in Mouse Hearts"],"prefix":"10.3390","volume":"25","author":[{"given":"Randall","family":"Loaiza","sequence":"first","affiliation":[{"name":"Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"CENIBiot Laboratory, The National Center of High Technology (CeNAT-CONARE), San Jos\u00e9 10109, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0793-3885","authenticated-orcid":false,"given":"Fatemeh","family":"Fattahi","sequence":"additional","affiliation":[{"name":"Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Kalbitz","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, 89081 Ulm, Germany"},{"name":"Military Medical City Hospital, Doha 486441, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamison J.","family":"Grailer","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"name":"Integrated Biology R&D, Bioassay Development, Promega Corporation, Madison, WI 53711, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Jalife","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1231-6267","authenticated-orcid":false,"given":"Hector H.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Medicine, Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firas S.","family":"Zetoune","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1285-8365","authenticated-orcid":false,"given":"Peter A.","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1161\/CIRCULATIONAHA.106.678359","article-title":"Sepsis and the heart","volume":"116","author":"Merx","year":"2007","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.7326\/0003-4819-113-3-227","article-title":"Septic shock in humans. 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