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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn348
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Regulation of the ankyrin-B-based targeting pathway following myocardial infarction

Thomas J. Hund1, Patrick J. Wright1, Wen Dun3, Jedidiah S. Snyder1, Penelope A. Boyden3 and Peter J. Mohler1,2

1 Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine Iowa City, IA
2 Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine Iowa City, IA
3 Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY 10032

Address correspondence to: Thomas J. Hund, Ph.D., Department of Internal Medicine, 285 Newton Road, CBRB 2283, University of Iowa Carver College of Medicine, Iowa City, IA 52242, Email: thomas-hund{at}uiowa.edu, P: +1 319-335-9691; F: +1 319-353-5552

Aims: Ion channel reorganization is a critical step in the pro-arrhythmogenic remodeling process that occurs in heart disease. Ankyrin-B (AnkB) is required for targeting and stabilizing ion channels, exchangers, and pumps.  Despite a wealth of knowledge implicating the importance of AnkB in human cardiovascular physiology, nothing is known regarding the role of AnkB in common forms of acquired human disease.

Methods and Results-: We present the first report of AnkB regulation following myocardial infarction. AnkB protein levels were reduced in the infarct border zone five days following coronary artery occlusion in the canine. We also observed a dramatic increase in AnkB mRNA levels five days post-occlusion. Surprisingly, expression of the upstream AnkB cytoskeletal component β2-spectrin was unchanged in post-infarct tissues. However, protein levels and/or membrane expression of downstream AnkB-associated ion channels and transporters Na+/K+ ATPase, Na+/Ca2+ exchanger, and IP3 receptor were altered five days post-occlusion. Interestingly, protein levels of the protein phosphatase 2A, an AnkB-associated signaling protein, were significantly affected five days post-occlusion. AnkB and PP2A protein levels recovered by 14 days post-occlusion, while Na+/K+ ATPase levels recovered by two months post-occlusion.

Conclusion-: These findings reveal the first evidence of ankyrin remodeling following myocardial infarction, and suggest an unexpected divergence point for regulation between ankyrin- and the underlying cytoskeletal network. These findings suggest a logical, but unexpected molecular mechanism underlying ion channel and transporter remodeling following myocardial infarction.

KEYWORDS arrhythmia (mechanisms); infarction; remodeling; signal transduction; cytoskeleton

Time for primary review: 23 Days


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