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Mitogen-activated protein kinases control cardiac KChIP2 gene expression
1Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Circulation Research
|December 31, 2005
Summary
Cardiac hypertrophy reduces the transient outward K(+) current (Ito) by decreasing KChIP2 expression. This study reveals JNK and MEK-ERK pathways regulate KChIP2 mRNA levels in cardiac cells.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Ion Channel Regulation
Background:
- Cardiac hypertrophy is linked to reduced transient outward K(+) current (Ito) and decreased expression of Kv4.2/4.3 and KChIP2 subunits.
- Understanding the molecular mechanisms behind these changes is crucial for addressing cardiac dysfunction.
Purpose of the Study:
- To investigate the role of KChIP2 downregulation in hypertrophy-associated Ito reduction.
- To elucidate the signaling pathways controlling KChIP2 mRNA expression in cardiomyocytes.
Main Methods:
- Aorta constriction in rats and phenylephrine (PE) treatment in myocytes to induce hypertrophy.
- Quantitative analysis of KChIP2 mRNA and protein levels.
- Pharmacological inhibition and genetic manipulation of protein kinase C (PKC), MEK, and JNK pathways.
Main Results:
- KChIP2 mRNA and protein levels were significantly reduced in hypertrophied rat hearts and PE-treated myocytes.
- Activation of PKC by phorbol myristate (PMA) reduced KChIP2 mRNA, an effect blocked by MEK inhibition.
- JNK inhibition prevented PE-induced KChIP2 reduction, while MEK inhibition affected basal KChIP2 expression and PKC-mediated downregulation.
Conclusions:
- Downregulation of KChIP2 expression contributes significantly to the reduction in Ito density during cardiac hypertrophy.
- KChIP2 mRNA expression is regulated by both JNK and MEK-ERK pathways, with JNK mediating PE-induced effects and MEK-ERK influencing basal expression and PKC signaling.