Lijun Wang1,2, Ziyi Wang2,3, Xing Liu1, Yue Zhang1, Manman Wang4, Xue Liang1, Guangping Li1. 1. Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University Tianjin 300211, People's Republic of China. 2. Department of Emergency Medicine, Tianjin Medical University General Hospital Tianjin 300052, People's Republic of China. 3. School of Clinical Medicine, Tsinghua University Beijing 100084, People's Republic of China. 4. Department of Cardiology, Affiliated Hospital of Jining Medical University Jining 272000, Shandong, People's Republic of China.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. AJTR
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. AJTR
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