Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis
Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis
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DOI：
10.1016/j.yjmcc.2005.01.002
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发表时间：
2005-03-01
影响因子：
5
通讯作者：
Sharma, AC
中科院分区：
文献类型：
--
作者：
Gupta, A;Aberle, NS;Sharma, AC
我们假设内皮素转换酶-1 （ECE-1）活性的调节会影响p38-丝裂原活化蛋白激酶（p38-MAPK）的磷酸化，并在脓毒症期间增强成年大鼠心室肌细胞（ARVMs）的凋亡。通过外源性给药big内皮素-1 （bigET-1, 100 nM）和FR901533 （10 μ M）抑制ECE-1 24小时，可以提高ECE-1在ARVMs中的底物有效性，从而改变ECE-1在ARVMs中的活性。FR901533显著降低假手术组和脓毒症组ET-1的浓度。FR901533在脓毒症中降低p38-MAPK磷酸化，而在假手术组中没有。在两组中，BigET-1上调p38-MAPK磷酸化，导致细胞肥大，降低细胞活力，逆转fr901533诱导的p38-MAPK磷酸化下调。虽然FR901533不影响细胞横截面积，但显著降低了两组ARVM的活力。bigET-1、FR901533和FR901533预处理后再用bigET-1预处理可提高假性ARVMs的峰值缩短。然而，bigET-1或FR901533治疗本身并未改变感染性arvm的收缩性。脓毒性ARVM在1 h和24 h时caspase-3活性显著升高。用FR901533预处理可显著提高假手术组和脓毒症组的caspase-3活性。数据表明，biget -1诱导的脓毒性ARVM肥厚与ECE-1依赖性的p38-MAPK激活相关。结果表明，ARVM对bigET-1无应答性是由于ECE-1依赖性细胞凋亡。我们得出结论，ECE-1可能在脓毒症期间通过增加caspase-3活性和p38-MAPK磷酸化，在ARVM功能障碍中发挥关键作用。(c) 2005 Elsevier Ltd版权所有。
We hypothesized that modulation of endothelin-converting enzyme-1 (ECE-1) activity would affect phosphorylation of p38-mitogen activated protein kinase (p38-MAPK) and potentiate apoptosis in adult rat ventricular myocytes (ARVMs) during sepsis. The activity of ECE-1 in ARVMs was altered by increasing the substrate availability for ECE-1 by exogenous administration of bigendothelin-1 (bigET-1, 100 nM) and by inhibiting ECE-1 using FR901533 (10 mu M) for 24-h. FR901533 significantly decreased the concentration of ET-1 in both sham and sepsis groups. FR901533 decreased p38-MAPK phosphorylation in sepsis but not in sham group. BigET-1 upregulated p38-MAPK phosphorylation, produced hypertrophy, decreased cell viability and reversed FR901533-induced down-regulation of p38-MAPK phosphorylation in both groups. Although, FR901533 did not affect cell cross-sectional area, it significantly reduced the viability of ARVM in both groups. The peak shortening of sham ARVMs was elevated by bigET-1, FR901533 and pretreatment with FR901533 followed by bigET-1. However, the contractility of septic ARVMs was not altered by either bigET-1 or FR901533 treatments per se. Septic ARVM exhibited significantly increased caspase-3 activity at 1 and 24-h. Pretreatment with FR901533 significantly elevated caspase-3 activity in both sham and sepsis group. The data demonstrated that bigET-1-induced hypertrophy in septic ARVM correlates with an ECE-1 dependent-activation of p38-MAPK. The results suggest that non-responsiveness of ARVM to bigET-1 is due to ECE-1 dependent apoptosis. We concluded that ECE-1 may play a crucial role in ARVM dysfunction via increased caspase-3 activity and p38-MAPK phosphorylation during sepsis. (c) 2005 Elsevier Ltd. All rights reserved.