© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy
aDepartment of Medicine, Case Western Reserve University, Cleveland, OH 44106-5029, USA
bCenter for Cardiovascular Research, University of Rochester, Rochester, NY 14642, USA
cDepartment of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
dLung Biology Center, University of California at San Francisco, San Francisco, CA 94143, USA
takeishi{at}med.id.yamagata-u.ac.jp
* Corresponding author. Present address: The First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Tel.: +81-23-628-5302; fax: +81-23-628-5305
Objective: A new member of the MAP kinase family, big MAP kinase-1 (BMK1), has been recently identified to promote cell growth and attenuate apoptosis. P90 ribosomal S6 kinase (p90RSK), one of the potentially important substrates of extracellular signal regulated kinase (ERK), regulates gene expression in part via phosphorylation of CREB and the Na+/H+ exchanger. Recently, we have demonstrated that the activity of BMK1, Src (the upstream regulator of BMK1) and p90RSK was increased in hypertrophied myocardium induced by pressure-overload in the guinea pig. However, the abundance and activity of these kinases in human hearts are unknown. Methods: In addition to the three classical MAP kinases (ERK, p38 kinase, and c-Jun NH2-terminal kinase (JNK)), we examined the protein expression and activity of Src, BMK1, and p90RSK in explanted hearts from patients with dilated cardiomyopathy (n=9). Normal donor hearts, which were not suitable for transplant for technical reasons, were used as controls (n=5). Results: There were no significant differences in the levels of protein expression of these kinases between normal and failing hearts. ERK1/2 and p90RSK were activated in heart failure compared to control (P<0.01 and P<0.03, respectively), while the activity of p38 kinase was decreased (P<0.05) and the activity of JNK was unchanged in heart failure. By contrast, the activities of Src and BMK1 were significantly reduced in end-stage heart failure compared to normal donor hearts (P<0.05). Conclusion: These data suggest that multiple MAP kinases, p90RSK, and Src are differentially regulated in human failing myocardium of patients with idiopathic dilated cardiomyopathy and may be involved in the pathogenesis of this complex disease.
KEYWORDS Cardiomyopathy; Heart failure; Protein kinases; Signal transduction
1 Yasuchika Takeishi, Qunhua Huang, and Jun-ichi Abe contributed equally to this work.
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