anthrax lethal toxin suppresses murine cardiomyocyte contractile function and intracellular ca2+ handling via a nadph oxidase-dependent mechanism炭疽致命毒素抑制小鼠心肌细胞收缩功能和细胞内钙离子处理通过nadph oxidase-dependent机制.pdfVIP

Anthrax Lethal Toxin Suppresses Murine Cardiomyocyte Contractile Function and Intracellular Ca2+ Handling via a NADPH Oxidase-Dependent Mechanism 1 1 1 1 2 2 1 Machender R. Kandadi , Yinan Hua , Heng Ma , Qun Li , Shu-ru Kuo , Arthur E. Frankel , Jun Ren * 1 Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, Wyoming, United States of America, 2 Cancer Research Institute of Scott and White Memorial Hospital, Temple, Texas, United States of America Abstract Objectives: Anthrax infection is associated with devastating cardiovascular sequelae, suggesting unfavorable cardiovascular effects of toxins originated from Bacillus anthracis namely lethal and edema toxins. This study was designed to examine the direct effect of lethal toxins on cardiomyocyte contractile and intracellular Ca2+ properties. Methods: Murine cardiomyocyte contractile function and intracellular Ca2+ handling were evaluated including peak shortening (PS), maximal velocity of shortening/ relengthening ( 6 dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), intracellular Ca2+ rise measured as fura-2 fluorescent intensity (DFFI), and intracellular Ca2+ decay rate. Stress signaling and Ca2+ regulatory proteins were assessed using Western blot analysis. Results: In vitro exposure to a lethal toxin (0.05 – 50 nM) elicited a concentration-dependent depression on cardiomyocyte contractile and intracellular Ca2+ properties (PS, 6 dL/dt, DFFI), along with prolonged duration of contraction and intracellular Ca2+ decay, the effects of which were nullified by the NADPH oxidase inhibitor apocynin. The lethal toxin significantly