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Am J Physiol Heart Circ Physiol (January 28, 2005). doi:10.1152/ajpheart.00320.2004
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Submitted on March 30, 2004
Accepted on January 21, 2005

Molecular Mechanisms Underlying Potassium Current Down-regulation in Canine Tachycardia-Induced Heart Failure

Fadi G Akar1, Richard C Wu1, George J Juang1, Yanli Tian1, Miroslava Burysek1, Deborah DiSilvestre1, Wei Xiong1, Antonis A Armoundas1, and Gordon F Tomaselli1*

1 Cardiology, Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: gtomasel{at}jhu.edu.

Heart failure (HF) is characterized by marked prolongation of the action potential duration and a reduction in cellular repolarization reserve. These changes are caused, in large part, by HF-induced Potassium (K)-current down regulation. Molecular mechanisms underlying these changes remain uncertain. We determined whether down regulation of K currents in a canine model of tachycardia-induced HF is caused by altered expression of underlying {alpha} and {beta} K channel subunits encoding these currents. K channel subunit expression was quantified in normal and failing dogs at the mRNA and protein levels in epicardial (EPI), midmyocardial (MID), and endocardial (ENDO) layers of the left ventricle. Results: Analysis of mRNA and protein levels of candidate genes encoding the transient-outward K-current (Ito) revealed marked reductions in cKv4.3 expression in HF in EPI (44% mRNA, 39% protein), MID (52% mRNA, 34% protein), and ENDO (49% mRNA, 73% protein) layers, a paradoxical enhancement (41% EPI, 97% MID, 113% ENDO) in cKv1.4 protein levels, without significant changes in cKChIP2 expression. Expression of cKir2.1, the gene underlying IK1, was unaffected by HF at mRNA and protein levels despite significant reduction in IK1, while remarkably canine-ERG, encoding IKr, exhibited increased protein expression. HF was not accompanied by significant changes in cKvLQT1 or cMinK mRNA and protein levels. Conclusions: These data indicate that: 1) Down-regulation of Ito in HF is associated with decreased cKv4.3, and not cKv1.4 or cKChIP2. 2) Alterations in IKr, IKs and IK1 in non-ischemic dilated cardiomyopathy are not caused by changes in either transcript or immunoreactive protein levels of relevant channel subunits, suggesting post-translational modification of these currents by HF.




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