{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T11:01:09Z","timestamp":1777806069442,"version":"3.51.4"},"reference-count":66,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"British Heart Foundation","award":["PG\/14\/19\/30751"],"award-info":[{"award-number":["PG\/14\/19\/30751"]}]},{"name":"British Heart Foundation","award":["PG\/16\/65\/32313"],"award-info":[{"award-number":["PG\/16\/65\/32313"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Reduction in cardiac contractility is common in severe sepsis. However, the pathological mechanism is still not fully understood. Recently it has been found that circulating histones released after extensive immune cell death play important roles in multiple organ injury and disfunction, particularly in cardiomyocyte injury and contractility reduction. How extracellular histones cause cardiac contractility depression is still not fully clear. In this work, using cultured cardiomyocytes and a histone infusion mouse model, we demonstrate that clinically relevant histone concentrations cause significant increases in intracellular calcium concentrations with subsequent activation and enriched localization of calcium-dependent protein kinase C (PKC) \u03b1 and \u03b2II into the myofilament fraction of cardiomyocytes in vitro and in vivo. Furthermore, histones induced dose-dependent phosphorylation of cardiac troponin I (cTnI) at the PKC-regulated phosphorylation residues (S43 and T144) in cultured cardiomyocytes, which was also confirmed in murine cardiomyocytes following intravenous histone injection. Specific inhibitors against PKC\u03b1 and PKC\u03b2II revealed that histone-induced cTnI phosphorylation was mainly mediated by PKC\u03b1 activation, but not PKC\u03b2II. Blocking PKC\u03b1 also significantly abrogated histone-induced deterioration in peak shortening, duration and the velocity of shortening, and re-lengthening of cardiomyocyte contractility. These in vitro and in vivo findings collectively indicate a potential mechanism of histone-induced cardiomyocyte dysfunction driven by PKC\u03b1 activation with subsequent enhanced phosphorylation of cTnI. These findings also indicate a potential mechanism of clinical cardiac dysfunction in sepsis and other critical illnesses with high levels of circulating histones, which holds the potential translational benefit to these patients by targeting circulating histones and downstream pathways.<\/jats:p>","DOI":"10.3390\/ijms24043225","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T01:56:48Z","timestamp":1675735008000},"page":"3225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Extracellular Histone-Induced Protein Kinase C Alpha Activation and Troponin Phosphorylation Is a Potential Mechanism of Cardiac Contractility Depression in Sepsis"],"prefix":"10.3390","volume":"24","author":[{"given":"Simon T.","family":"Abrams","sequence":"first","affiliation":[{"name":"Department of Clinical Infection Microbiology and Immunology, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"Coagulation Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool L7 8XP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasir","family":"Alhamdi","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology and Immunology, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"Sheffield Teaching Hospital NHS Foundation Trust, Sheffield S5 7AU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4183-1818","authenticated-orcid":false,"given":"Min","family":"Zi","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, Centre for Cardiac Research, University of Manchester, Manchester M13 9PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengmei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology and Immunology, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"The Medical School, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology and Immunology, University of Liverpool, Liverpool L69 7BE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-3548","authenticated-orcid":false,"given":"Guozheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology and Immunology, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"Coagulation Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool L7 8XP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6836-7795","authenticated-orcid":false,"given":"Elizabeth J.","family":"Cartwright","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, Centre for Cardiac Research, University of Manchester, Manchester M13 9PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9708-8883","authenticated-orcid":false,"given":"Cheng-Hock","family":"Toh","sequence":"additional","affiliation":[{"name":"Department of Clinical Infection Microbiology and Immunology, University of Liverpool, Liverpool L69 7BE, UK"},{"name":"Roald Dahl Haemostasis & Thrombosis Centre, Royal Liverpool University Hospital, Liverpool L7 8XP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1164\/rccm.201504-0781OC","article-title":"Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. 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