Abstract
Aims: Myocardial 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 results: Lipopolysaccharide (LPS) increased MKP1 expression in the myocardium in vivo and in cultured neonatal cardiomyocytes in 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) 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-α expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice. Conclusion: LPS 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.
Original language | English |
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Pages (from-to) | 471-479 |
Number of pages | 9 |
Journal | Cardiovascular Research |
Volume | 93 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2012 |
Bibliographical note
Funding Information:This study was supported by operating grants from the Canadian Institutes of Health Research (MOP-14653 to Q.F.) and the National Institutes of Health (R01AI068956 to Y.L. and Q.F.). T.Z. was supported by an Ontario Graduate Scholarship. Q. F. is a Career Investigator of the Heart and Stroke Foundation of Ontario.
Keywords
- Cardiac function
- Lipopolysaccharide
- MKP1
- Sepsis
- TNF-α
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
- Physiology (medical)