Impaired JAK2-induced activation of STAT3 in failing human myocytes
Impaired JAK2-induced activation of STAT3 in failing human myocytes
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DOI：
10.1039/c2mb25120e
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Modesti, Pietro Amedeo
中科院分区：
文献类型：
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作者：
Cambi, Giulia Elisa;Lucchese, Gianluca;Modesti, Pietro Amedeo
虽然血管紧张素（Ang）II诱导的Janus激活的激酶（JAK）2磷酸化被报道在失败的人心肌细胞中增强，但心脏保护（信号转导子和转录激活因子-STAT 3）和促炎（STAT 2和STAT 5）反应之间的下游平衡仍未被探索。因此，在从衰竭的人心脏（n = 16）和从人（假定的供体，n = 6）或成年大鼠的非衰竭（NF）心脏获得的分离的心肌细胞中研究了JAK 2活化后的STAT磷酸化和假定的基因过表达。在NF肌细胞中，Ang II诱导的JAK 2活化之后是STAT 3磷酸化（30 min时为186 +/- 45%），无STAT 2或STAT 5反应。相关的B细胞淋巴瘤（Bcl）-xL过表达JAK 2和细胞外信号调节激酶（ERK）1/2抑制剂均能消除（1.05 ± 0.39倍）（分别为AG 490，10 μ M和PD 98059，30 μ M），而Fas配体（Fas-L）反应（0.91 +/-0.21倍）仅被p38 MAPK拮抗剂（SB 203580，10 μ M）抑制。在衰竭的心肌细胞中，Ang II诱导的JAK 2激活之后是STAT 2（237 +/- 38%）和STAT 5（222 +/- 31%）磷酸化，没有STAT 3反应。没有观察到Bcl-xL表达的变化，并且相关的Fas-L基因过表达（1.14 +/- 0.27倍）被p38丝裂原活化蛋白激酶（MAPK）拮抗作用消除。JAK 2诱导的STATs反应在人类衰竭心肌细胞中的改变可能与心力衰竭中心功能障碍的进展有关。
Although angiotensin (Ang) II-induced Janus-activated kinase (JAK) 2 phosphorylation was reported to be enhanced in failing human cardiomyocytes, the downstream balance between cardio-protective (signal transducer and activator of transcription-STAT3) and the pro-inflammatory (STAT2 and STAT5) response remains unexplored. Therefore STATs phosphorylation and putative genes overexpression following JAK2 activation were investigated in isolated cardiomyocytes obtained from failing human hearts (n = 16), and from non-failing(NF) hearts of humans (putative donors, n = 6) or adult rats. In NF myocytes Ang II-induced JAK2 activation was followed by STAT3 phosphorylation (186 +/- 45% at 30 min), with no STAT2 or STAT5 response. The associated B cell lymphoma (Bcl)-xL overexpression (1.05 +/- 0.39 fold) was abolished by both JAK2 and extracellular signal-regulated kinase (ERK) 1/2 inhibitors (AG490, 10 mu M, and PD98059, 30 mu M, respectively), whereas Fas ligand (Fas-L) response (0.91 +/- 0.21 fold) was inhibited only by p38MAPK antagonism (SB203580, 10 mu M). In failing myocytes Ang II-induced JAK2 activation was followed by STAT2 (237 +/- 38%) and STAT5 (222 +/- 31%) phosphorylation, with no STAT3 response. No changes in Bcl-xL expression were observed, and the associated Fas-L gene overexpression (1.14 +/- 0.27 fold) being abolished by p38 mitogen-activated protein kinase (MAPK) antagonism. The altered JAK2 induced STATs response in human failing cardiomyocytes may be of relevance for the progression of cardiac dysfunction in heart failure.