ArticleCardiovascular research2012
Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-α expression and improves cardiac function during endotoxemia.
Article in Cardiovascular research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 34 citations in OpenAlex.
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- Protective effects of rolipram on endotoxic cardiac dysfunction via inhibition of the inflammatory response in cardiac fibroblasts.BMC cardiovascular disorders · 2020Article
- MAP kinase phosphatase-1, a gatekeeper of the acute innate immune response.Life sciences · 2020Review
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- Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice.The American journal of pathology · 2015Article
- Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
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- Unique catalytic activities and scaffolding of p21 activated kinase-1 in cardiovascular signaling.Frontiers in pharmacology · 2013Review
- The Toll-like receptor 9 ligand, CpG oligodeoxynucleotide, attenuates cardiac dysfunction in polymicrobial sepsis, involving activation of both phosphoinositide 3 kinase/Akt and extracellular-signal-related kinase signaling.The Journal of infectious diseases · 2013Article
- MAPK signaling drives inflammation in LPS-stimulated cardiomyocytes: the route of crosstalk to G-protein-coupled receptors.PloS one · 2012Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
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 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.
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.
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