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: Miriam Kalbitz, Jamison J Grailer, Fatemeh Fattahi, Lawrence Jajou, Todd J Herron, Katherine F Campbell, Firas S Zetoune, Markus Bosmann, J Vidya Sarma, Markus Huber-Lang, Florian Gebhard, Randall Loaiza, Hector H Valdivia, José Jalife, Mark W Russell, Peter A Ward
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 5 Pg. 2185-93 (May 2015) ISSN: 1530-6860 [Electronic] United States
• PMID: 25681459 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Carrier Proteins
• Histones
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Reactive Oxygen Species
• Receptor, Anaphylatoxin C5a
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Caspase 1
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cardiomyopathies (blood, diagnosis, etiology)
• Carrier Proteins (physiology)
• Caspase 1 (physiology)
• Cells, Cultured
• Disease Models, Animal
• Histones (adverse effects, blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (metabolism, pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Receptor, Anaphylatoxin C5a (metabolism)
• Sepsis (blood, complications, pathology)
• Toll-Like Receptor 2 (physiology)
• Toll-Like Receptor 4 (physiology)