p38 MAPK inhibition decreases TNF-α production and enhances postischemic human myocardial function
p38 MAPK inhibition decreases TNF-α production and enhances postischemic human myocardial function
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DOI：
10.1006/jsre.1998.5548
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发表时间：
1999-05-01
影响因子：
2.2
通讯作者：
Harken, AH
中科院分区：
文献类型：
--
作者：
Cain, BS;Meldrum, DR;Harken, AH
导论. TNF-α是一种促炎细胞因子，与缺血/再灌注（I/R）后的心肌功能障碍有关。I/R导致心肌产生TNF-α，TNF-α抑制心肌收缩力，p38丝裂原活化蛋白激酶（MAPK）是一种氧化还原敏感性蛋白激酶，参与导致TNF-α产生的细胞内信号传导。目前尚不清楚人心脏在I/R后是否产生TNF-α，如果是，是否涉及p38 MAPK。p38 MAPK抑制通过抑制心肌TNF-α的产生增强人心肌IIR后收缩功能。将人心房小梁悬浮在器官浴中，以1 Hz模拟场，并记录力的发展。平衡90分钟后，在模拟缺血（缺氧45分钟，无基质，以3 Hz快速起搏）之前，将小梁暴露于p38 MAPM抑制剂（SB 203580，1 μ M）或载体（n = 6），然后再复氧120分钟。采用酶联免疫吸附试验（ELISA）检测心肌TNF-α水平。I/R使人心肌TNF-α水平从26.9 ± 9.3 pg/g湿组织增加到83.9 ± 19.2 pg/g湿组织（P < 0.05灌注vs I/R; ANOVA Bonferroni/Dunn），而p38 MAPK抑制使I/R后心肌TNF-α水平降低到32.3 ± 8.0 pg/g湿组织（P > 0.05 p38 MAPK抑制vs I/R）。p38 MAPK抑制改善缺血后力的发展，从18.5 +/- 2.1到37.0 +/- 2.0%基线发展力（%BDF; P < 0.05 I/R vs p38 MAPK抑制）。(1)人心脏在I/R后产生TNF-α，（2）p38 MAPK介导心肌I/R诱导的TNF-α产生，（3）p38 MAPK抑制限制I/R后的功能损害，和（4）抑制缺血诱导的TNF-α产生可能代表用于改善血管成形术、冠状动脉旁路术或心脏移植后的心肌功能的有效治疗策略。(C)北京：科学出版社.
Introduction. TNF-alpha is a proinflammatory cytokine implicated in myocardial dysfunction following ischemia/reperfusion (I/R). I/R results in myocardial production of TNF-alpha and TNF-alpha suppresses myocardial contractility, p38 mitogen-activated protein kinase (MAPK) is a redox-sensitive protein kinase involved in intracellular signaling leading to TNF-alpha production. It remains unknown if the human heart produces TNF-alpha after I/R and, if so, whether p38 MAPK is involved.Hypothesis. p38 MAPK inhibition enhances human myocardial post-IIR contractile function by inhibition of myocardial TNF-alpha production.Methods. Human atrial trabeculae were suspended in organ baths, field simulated at 1 Hz, and force development was recorded. Following a 90-min equilibration, trabeculae were exposed to a p38 MAPM inhibitor (SB 203580, 1 mu M) or vehicle teach n = 6) prior to simulated ischemia (45 min hypoxia, substrate-free, rapid pacing at 3 Hz) followed by 120 min reoxygenation. Myocardial TNF-alpha levels were measured by ELISA at end reoxygenation.Results. I/R increased human myocardial TNF-alpha levels from 26.9 +/- 9.3 to 83.9 +/- 19.2 pg/g wet tissue (P < 0.05 perfusion vs I/R; ANOVA Bonferroni/Dunn), while p38 MAPK inhibition decreased post-I/R myocardial TNF-alpha levels to 32.3 +/- 8.0 pg/g wet tissue (P > 0.05 p38 MAPK inhibition vs I/R). p38 MAPK inhibition improved postischemic force development from 18.5 +/- 2.1 to 37.0 +/- 2.0% baseline developed force (%BDF; P < 0.05 I/R vs p38 MAPK inhibition).Conclusions. (1) The human heart produces TNF-alpha after I/R, (2) p38 MAPK mediates myocardial I/R- induced TNF-alpha production, (3) p38 MAPK inhibition limits functional impairment after I/R, and (4) inhibition of ischemia-induced TNF-alpha production may represent a potent therapeutic strategy for improving myocardial function after angioplasty, coronary bypass, or heart transplantation. (C) 1999 Academic Press.