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p38 mitogen activated protein kinase mediates both death signaling and functional depression in the heart
被引:63
作者:
Wang, MJ
Tsai, BM
Turrentine, MW
Mahomed, Y
Brown, JW
Meldrum, DR
机构:
[1] Indiana Univ, Sch Med, Dept Surg, Sect Cardiothorac Surg, Indianapolis, IN 46202 USA
[2] Indiana Univ, Sch Med, Dept Cellular & Integrat Physiol, Sect Cardiothorac Surg, Indianapolis, IN 46202 USA
[3] Indiana Univ, Sch Med, Indiana Ctr Vasc Biol & Med, Indianapolis, IN 46202 USA
关键词:
D O I:
10.1016/j.athoracsur.2005.05.070
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Background. Understanding the myocardial inflammatory response to ischemia is an important part of achieving the elusive clinical goal of long-enduring myocardial protection. p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant stress-induced myocardial tumor necrosis factor production. However, it is unknown whether p38 MAPK mediates the following important events in both myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3, and caspase-11 activation, and tumor necrosis factor, interleukin-1 beta and interleukin-6 production. Methods. Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20 mu M SB203580 (p38 MAPK inhibitor). Myocardial functional measurements were continuously recorded throughout the experiments. Myocardial tissue was then assessed for products of p38 MAPK activation, expression of tumor necrosis factor, interleukin-1 beta and interleukin-6, and activation of caspase-1, caspase-3 and caspase-11. Results. Postischemic recovery of left ventricular developed pressure, +dP/dt and -dP/dt was significantly increased by p38 MAPK inhibition (MKI) (left ventricular developed pressure: 48.4 +/- 3.87 MKI versus 32.7 +/- 4.32 mm Hg; +dP/dt: 1392.0 +/- 141.7 MKI versus 896.7 +/- 128.5 mm Hg/s; -dP/dt: -889.9 97.63 MKI versus -548.9 +/- 71.29 mmHg/s). p38 MAPK inhibition also significantly reduced ischemia-reperfusion-induced elevation of left ventricular end-diastolic pressure (82.76 +/- 4.59 MKI vs 69.95 +/- 3.55 mm Hg). p38 MKI decreased myocardial tumor necrosis factor, interleukin-1 beta and interleukin-6 protein levels, and reduced active myocardial caspase-1, caspase-3 and caspase-11. Conclusions. The p38 MAPK pathway indeed mediates the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3 and caspase-11 activation, and tumor necrosis factor, interleukin-1 beta, interleukin-6 production after myocardial ischernia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.
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页码:2235 / 2241
页数:7
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