Effects of extracellular histones on left ventricular diastolic function and potential mechanisms in mice with sepsis.

Extracellular histone (EH) is involved in the development of septic myocardial injury (SMI). In this study, we explored whether EH could induce left ventricular diastolic dysfunction (LVDD) in sepsis, and investigated the potential mechanisms through in vivo and in vitro experiments using animal models. The ratio between E-wave and A-wave (E/A ratio), left ventricular end diastolic volume, and isovolumic relaxation time (IVRT) were measured in cecal ligation and perforation (CLP)- and EH-treated male C57BL/6J mice using echocardiography. The protein and mRNA levels of apoptosis-related proteins (cleaved caspase-3, Bcl-2, and Bax) and cardiac troponin T (cTnT) in the left ventricular tissue/cardiomyocytes were measured using enzyme-linked immunosorbent assay, qRT-PCR, and western blotting. Cardiomyocyte apoptosis was detected by flow cytometry. CLP mice presented with LVDD, which was accompanied by increased circulating histones, cTnT and Bax protein levels. Circulating histones were correlated with cTnT, Bax, IVRT, and E/A ratio in CLP mice. Intraperitoneal injection of EH resulted in LVDD in mice. EH induced cardiomyocyte apoptosis, and histone neutralizing agents improved SMI and protected mice against CLP- and EH-induced death. EH is involved in septic LVDD, and this alteration might be associated with EH-induced apoptosis. EH may serve as a potential therapeutic target for SMI.