Differential regulation of mitogen-activated protein kinases in the failing human heart in response to mechanical unloading
Differential regulation of mitogen-activated protein kinases in the failing human heart in response to mechanical unloading
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DOI：
10.1161/hc4401.099449
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发表时间：
2001-11-06
期刊：
影响因子：
37.8
通讯作者：
Mann, DL
中科院分区：
文献类型：
--
作者：
Flesch, M;Margulies, KB;Mann, DL
背景-用左心室辅助装置（LVAD）对心脏进行机械卸载会导致衰竭心肌细胞的生物学发生有利的变化。为了确定这些改善的潜在机制，我们检查了在存在和不存在 LVAD 支持的情况下衰竭心脏中丝裂原激活蛋白激酶 (MAPK) 的调节。方法和结果 - 我们检查了 p44/42 细胞外调节激酶、p38 激酶和 c-Jun N 末端激酶的激活程度（即磷酸化） (JNK1/2)，以及从 11 名接受 LVAD 支持的患者和 11 名未接受 LVAD 支持的患者获得的心肌样本中这些 MAPK 的相应活性水平。还检查了另外 6 名患者的 MAPK 活性，这些患者在 LVAD 支持之前和之后获得了配对样本。 LVAD支持后p44/42和JNK1/2的活性显着降低，而p38活性水平显着升高。我们检查了与 MAPK 激活相关的功能参数，即心肌细胞肥大和凋亡。 LVAD 支持后，心肌细胞大小和心肌细胞凋亡发生率均显着降低。结论：衰竭心脏的机械卸载导致 MAPK 的差异调节。 MAPK 活性的这些变化与心肌细胞肥大和活力的变化相关，这表明 LVAD 支持后观察到的一些有益变化的潜在机制基础。
Background-Mechanical unloading of the heart with a left ventricular assist device (LVAD) leads to favorable changes in the biology of the failing cardiac myocyte. To determine a potential mechanism for these improvements, we examined the regulation of mitogen-activated protein kinases (MAPKs) in the failing heart in the presence and absence of LVAD support.Methods and Results-We examined the degree of activation (ie, phosphorylation) of p44/42 extracellularly regulated kinase, p38 kinase, and c-Jun N-terminal kinase (JNK1/2), and the corresponding activity levels of these MAPKs in myocardial samples obtained from 11 patients with LVAD support and in 11 patients without LVAD support. MAPK activity was also examined in an additional 6 patients from whom paired samples were obtained before and after LVAD support. The activity of p44/42 and JNK1/2 were reduced significantly, whereas p38 activity levels were significantly increased after LVAD support. We examined functional parameters that are linked to MAPK activation, namely cardiac myocyte hypertrophy and apoptosis. Both cardiac myocyte cell size and the incidence of cardiac myocyte apoptosis were significantly reduced after LVAD support.Conclusions-Mechanical unloading of the failing heart leads to differential regulation of MAPKs. These changes in MAPK activity are associated with changes in myocyte hypertrophy and viability, suggesting a potential mechanistic basis for some of the observed salutary changes after LVAD support.