Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction
Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction
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DOI：
10.1161/circulationaha.104.490979
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发表时间：
2005-05-24
期刊：
影响因子：
37.8
通讯作者：
Neviere, R
中科院分区：
文献类型：
--
作者：
Lancel, S;Joulin, O;Neviere, R
背景 - 尽管脓毒症诱导的细胞凋亡的大部分有害影响归因于淋巴细胞死亡增加，但半胱天冬酶激活可能直接改变不同器官系统的细胞功能。我们推测左心室 (LV) 心肌细胞 caspase 激活直接参与脓毒症引起的心脏收缩功能障碍。 方法和结果 - 大鼠注射内毒素 (10 mg/kg) 处理 4 小时后分离的 LV 心肌细胞显示收缩储备和肌丝对 Ca2+ 的反应显着降低。与此同时，内毒素还诱导左心室心肌细胞 caspase-3、-8 和 -9- 样活性增加，这与肌节结构破坏和心肌丝成分裂解有关。有趣的是，zVAD。 fmk 治疗脓毒症大鼠可预防左心室心肌细胞收缩功能障碍、肌丝对钙的反应减少、肌钙蛋白 T 裂解和肌小节破坏。内毒素处理大鼠的血清（10%）诱导收缩功能障碍、caspase-3样活性增加以及初始左心室心肌细胞的肌钙蛋白T裂解。从 zVAD 中分离出的左心室心肌细胞可以防止脓毒症血清的影响。 fmk- 或 zDEVD。 cmk 处理的大鼠或用 zVAD 预孵育的 LV 心肌细胞。 fmk 或 zDEVD。 cmk.结论 - 结果显示内毒素诱导的 caspase 激活与单个 LV 心肌细胞水平的收缩储备减少和肌节紊乱之间存在重要关系。
Background - Although most of the deleterious effects of sepsis- induced apoptosis have been attributed to increased lymphocyte cell death, caspase activation may directly alter cell function of different organ systems. We postulated that left ventricular ( LV) cardiomyocyte caspase activation is directly involved in sepsis- induced heart contractile dysfunction.Methods and Results - LV cardiomyocytes isolated 4 hours after rat treatment with endotoxin injection ( 10 mg/ kg) displayed major reductions in contractile reserve and myofilament response to Ca2+. Concomitantly, endotoxin also induced increases in LV cardiomyocyte caspase- 3, - 8, and - 9- like activities, which were associated with sarcomeric structure destruction and cleavage of components of the cardiac myofilament. Interestingly, zVAD. fmk treatment of septic rat prevented LV cardiomyocyte contractile dysfunction, reductions in myofilament response to calcium, troponin T cleavage, and sarcomere destruction. Serum ( 10%) of endotoxin- treated rats induced contractile dysfunction, caspase- 3 - like activity increase, and troponin T cleavage of naive LV cardiomyocytes. The effects of septic serum were prevented in LV cardiomyocytes isolated from zVAD. fmk- or zDEVD. cmk- treated rats or LV cardiomyocytes preincubated with zVAD. fmk or zDEVD. cmk.Conclusions - The results show an important relationship between endotoxin- induced caspase activation and reduced contractile reserve and sarcomere disarray at the level of single LV cardiomyocytes.