TY - JOUR
T1 - Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy
AU - Takeishi, Yasuchika
AU - Huang, Qunhua
AU - Abe, Jun Ichi
AU - Che, Wenyi
AU - Lee, Jiing Dwan
AU - Kawakatsu, Hisaaki
AU - Hoit, Brian D.
AU - Berk, Bradford C.
AU - Walsh, Richard A.
N1 - Funding Information:
The authors wish to thank Dr C. Yan for their invaluable assistance and critical reading of this manuscript. This study was supported by grants from National Institutes of Health (HL44721 and HL49192 to B.C. Berk, HL52318 to R.A. Walsh, and HL66919 to J. Abe), a grant-in-aid for Scientific Research (No. 12770337 to Y.T.) from the Ministry of Education, Science, Sports and Culture, Japan, and a grant from Kanae Foundation (to Y.T.).
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Cardiomyopathy
KW - Heart failure
KW - Protein kinases
KW - Signal transduction
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U2 - 10.1016/S0008-6363(01)00438-2
DO - 10.1016/S0008-6363(01)00438-2
M3 - Article
C2 - 11744021
AN - SCOPUS:0036135724
SN - 0008-6363
VL - 53
SP - 131
EP - 137
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -