title: Role of extracellular histones in the cardiomyopathy of sepsis.
abstract: The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca(2+)]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nacht-, LRR-, and PYD-domains-containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca(2+)]i, as well as defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Miriam
authors: M
authors: Kalbitz
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Jamison J
authors: JJ
authors: Grailer
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Fatemeh
authors: F
authors: Fattahi
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Lawrence
authors: L
authors: Jajou
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Todd J
authors: TJ
authors: Herron
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Katherine F
authors: KF
authors: Campbell
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Firas S
authors: FS
authors: Zetoune
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Markus
authors: M
authors: Bosmann
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: J Vidya
authors: JV
authors: Sarma
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Markus
authors: M
authors: Huber-Lang
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Florian
authors: F
authors: Gebhard
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Randall
authors: R
authors: Loaiza
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Hector H
authors: HH
authors: Valdivia
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: José
authors: J
authors: Jalife
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany.
authors: Mark W
authors: MW
authors: Russell
authors: *Department of Pathology and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, USA; and Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany pward@umich.edu.
authors: Peter A
authors: PA
authors: Ward
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D002352:Carrier Proteins / Q000502:physiology; D020170:Caspase 1 / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006657:Histones / Q000009:adverse effects* / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000150:complications* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D006657:Histones; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D044087:Receptor, Anaphylatoxin C5a; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020170:Caspase 1; D002118:Calcium
keywords: NLRP3 inflammasome; cardiomyocytes; complement; echocardiogram/Doppler; polymicrobial sepsis