| First Author | Zhang T | Year | 2012 |
| Journal | Cardiovasc Res | Volume | 93 |
| Issue | 3 | Pages | 471-9 |
| PubMed ID | 22198506 | Mgi Jnum | J:194710 |
| Mgi Id | MGI:5474541 | Doi | 10.1093/cvr/cvr346 |
| Citation | Zhang T, et al. (2012) Mitogen-activated protein kinase phosphatase-1 inhibits myocardial TNF-alpha expression and improves cardiac function during endotoxemia. Cardiovasc Res 93(3):471-9 |
| abstractText | AIMS: Myocardial tumour necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha 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-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. |
