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MKP1 inhibits myocardial TNF‐alpha expression and improves cardiac function in endotoxemia
Author(s) -
Lu Xiangru,
Zhang Ting,
Arnold Paul,
Liu Yusen,
Feng Qingping
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb665
Subject(s) - p38 mitogen activated protein kinases , biology , pak1 , lipopolysaccharide , tumor necrosis factor alpha , messenger rna , rac1 , kinase , microbiology and biotechnology , endocrinology , signal transduction , protein kinase a , biochemistry , gene
The objective of this study was to investigate the role of mitogen‐activated protein kinase phosphatase‐1 (MKP1) pathway in myocardial tumor necrosis factor (TNF)‐alpha expression and cardiac function during endotoxemia. Experiments were carried out in a mouse model of endotoxemia and in cultured neonatal cardiomyocytes. Lipopolysaccharide (LPS) increased MKP1 expression in the heart and in cultured neonatal cardiomyocytes. LPS‐induced ERK1/2 and p38 phosphorylation in the myocardium was prolonged in MKP1 −/− mice. Myocardial TNF‐alpha mRNA and protein levels were enhanced in MKP1 −/− compared to WT mice in endotoxemia, leading to a further decrease in cardiac function. Inhibition of Rac1 and PAK1 by a dominant negative Rac1 adenovirus (Ad‐Rac1N17) and PAK1 siRNA, respectively blocked LPS‐induced MKP1 expression in cardiomyocytes. PAK1 siRNA also decreased p38 and c‐Jun N‐terminal kinase (JNK) activation, and TNF‐alpha expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice. In conclusion, LPS increases myocardial MKP1 expression via JNK1. MKP1 attenuates ERK1/2 and p38 activation, inhibits myocardial TNF‐alpha expression and improves cardiac function in endotoxemia. Thus, MKP1 represents an important negative feedback mechanism limiting pro‐inflammatory response in the heart during sepsis.