Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-α expression and improves cardiac function during endotoxemia.
Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-α expression and improves cardiac function during endotoxemia.
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丝裂原激活蛋白激酶磷酸酶-1 抑制心肌 TNF-α 表达并改善内毒素血症期间的心脏功能。
DOI：
10.1093/cvr/cvr346
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发表时间：
2012
影响因子：
10.8
通讯作者：
Feng,Qingping
中科院分区：
文献类型：
--
作者：
Zhang,Ting;Lu,Xiangru;Arnold,Paul;Liu,Yin;Baliga,Reshma;Huang,Hong;Bauer,JohnAnthony;Liu,Yusen;Feng,Qingping
目的研究内毒素血症时心肌肿瘤坏死因子-α（TNF-α）表达对心功能的影响。本研究旨在探讨内毒素血症时丝裂原活化蛋白激酶磷酸酶1（mitogen-activated protein kinase phosphatase-1，MKP 1）通路在心肌TNF-α表达及心功能中的作用。LPS诱导的心肌细胞外信号调节激酶（ERK）1/2和p38磷酸化在MKP 1 −/−小鼠中延长。与内毒素血症野生型（WT）小鼠相比，MKP 1 −/−小鼠心肌TNF-α mRNA和蛋白水平升高，导致心脏功能进一步下降。为了研究Rac 1/p21激活激酶1（PAK 1）信号传导是否调节MKP 1表达，用LPS处理心肌细胞。分别用显性失活Rac 1腺病毒（Ad-Rac 1 N17）和PAK 1 siRNA抑制Rac 1和PAK 1，可阻断LPS诱导的心肌细胞MKP 1表达，PAK 1 siRNA还可抑制LPS诱导的p38和c-Jun N末端激酶（JNK）活化以及TNF-α表达。此外，无论是Rac 1或JNK 1的缺陷降低心肌MKP 1的表达在endotoxemic mice.ConclusionLPS激活Rac 1/PAK 1途径，增加心肌MKP 1的表达通过JNK 1。MKP 1可减弱ERK 1/2和p38的激活，抑制心肌TNF-α的表达，改善内毒素血症时的心功能。因此，MKP 1代表了在脓毒症期间限制心脏中的促炎反应的重要负反馈机制。
AimsMyocardial tumour necrosis factor-α (TNF-α) expression induces cardiac dysfunction in endotoxemia. The aim of this study was to investigate the role of mitogen-activated protein kinase phosphatase-1 (MKP1) pathway in myocardial TNF-α expression and cardiac function during endotoxemia.Methods and resultsLipopolysaccharide (LPS) increased MKP1 expression in the myocardiumin vivoand in cultured neonatal cardiomyocytesin vitro. LPS-induced extracellular signal-regulated kinase (ERK) 1/2 and p38 phosphorylation in the myocardium was prolonged in MKP1−/−mice. Myocardial TNF-α mRNA and protein levels were enhanced in MKP1−/−compared with wild-type (WT) mice in endotoxemia, leading to a further decrease in cardiac function. To study if Rac1/p21-activated kinase 1 (PAK1) signalling regulates MKP1 expression, cardiomyocytes were treated with LPS. Inhibition of Rac1 and PAK1 by a dominant negative Rac1 adenovirus (Ad-Rac1N17) andPAK1siRNA, respectively, blocked LPS-induced MKP1 expression in cardiomyocytes.PAK1siRNA also decreased p38 and c-Jun N-terminal kinase (JNK) activation, and TNF-α expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice.ConclusionLPS activates the Rac1/PAK1 pathway, which increases myocardial MKP1 expression via JNK1. MKP1 attenuates ERK1/2 and p38 activation, inhibits myocardial TNF-α expression, and improves cardiac function in endotoxemia. Thus, MKP1 represents an important negative feedback mechanism limiting pro-inflammatory response in the heart during sepsis.