Published online before print December 29, 2005, doi: 10.1161/01.RES.0000201956.86258.e1
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Submitted on February 16, 2005
Revised on November 9, 2005
Accepted on December 16, 2005
Mitogen-Activated Protein Kinases Control Cardiac KChIP2 Gene Expression
Ying Jia and Koichi Takimoto *
From the Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pa.
* To whom correspondence should be addressed. E-mail: koichi{at}pitt.edu.
Hypertrophied myocardium is associated with reductions in the transient outward K+ current (Ito) and expression of pore-forming Kv4.2/4.3 and auxiliary KChIP2 subunits. Here we show that KChIP2 mRNA and protein levels are dramatically decreased to 10% to 30% of control levels in the left ventricle of aorta-constricted rats in vivo and phenylephrine (PE)-treated myocytes in vitro. PE also markedly decreases Ito density. Inhibition of protein kinase Cs (PKCs) does not affect the PE-induced reduction in KChIP2 mRNA level, whereas activation of PKC with phorbol ester (phorbol myristate [PMA]) causes a marked reduction in KChIP2 mRNA level. Pharmacological inhibition of MEKs or overexpression of a dominant-negative MEK1 increases the basal KChIP2 mRNA expression and blocks the PMA-induced decrease in auxiliary subunit mRNA level. In addition, a constitutively active MEK1 decreases the basal KChIP2 mRNA level, and PMA causes no further reduction in auxiliary subunit mRNA level in active MEK1-expressing cells. Furthermore, pharmacological inhibition of JNKs or overexpression of a dominant-negative JNK1 prevents the PE-induced, but not PMA-induced, reduction in KChIP2 mRNA expression. These results suggest that downregulation of KChIP2 expression significantly contributes to the hypertrophy-associated reduction in Ito density. They also indicate that the expression of KChIP2 mRNA is controlled by the 2 branches of mitogen-activated protein kinase pathways: JNKs play a predominant role in mediating the PE-induced reduction, whereas the MEK-ERK pathway influences the basal expression and mediates the PKC-mediated downregulation.
Key words: cardiac hypertrophy • voltage-gated K+ channel • signal transduction • gene regulation
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