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Heart Rhythm. 2012 May;9(5):812-20. doi: 10.1016/j.hrthm.2011.11.055. Epub 2011 Dec 2.

BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes.

Author information

  • 1Cardiovascular Research Institute, University of California, San Francisco, CA, USA.

Abstract

BACKGROUND:

Heart failure is a growing epidemic, and a typical aspect of heart failure pathophysiology is altered calcium transients. Normal cardiac calcium transients are initiated by Cav1.2 channels at cardiac T tubules. Bridging integrator 1 (BIN1) is a membrane scaffolding protein that causes Cav1.2 to traffic to T tubules in healthy hearts. The mechanisms of Cav1.2 trafficking in heart failure are not known.

OBJECTIVE:

To study BIN1 expression and its effect on Cav1.2 trafficking in failing hearts.

METHODS:

Intact myocardium and freshly isolated cardiomyocytes from nonfailing and end-stage failing human hearts were used to study BIN1 expression and Cav1.2 localization. To confirm Cav1.2 surface expression dependence on BIN1, patch-clamp recordings were performed of Cav1.2 current in cell lines with and without trafficking-competent BIN1. Also, in adult mouse cardiomyocytes, surface Cav1.2 and calcium transients were studied after small hairpin RNA-mediated knockdown of BIN1. For a functional readout in intact heart, calcium transients and cardiac contractility were analyzed in a zebrafish model with morpholino-mediated knockdown of BIN1.

RESULTS:

BIN1 expression is significantly decreased in failing cardiomyocytes at both mRNA (30% down) and protein (36% down) levels. Peripheral Cav1.2 is reduced to 42% by imaging, and a biochemical T-tubule fraction of Cav1.2 is reduced to 68%. The total calcium current is reduced to 41% in a cell line expressing a nontrafficking BIN1 mutant. In mouse cardiomyocytes, BIN1 knockdown decreases surface Cav1.2 and impairs calcium transients. In zebrafish hearts, BIN1 knockdown causes a 75% reduction in calcium transients and severe ventricular contractile dysfunction.

CONCLUSIONS:

The data indicate that BIN1 is significantly reduced in human heart failure, and this reduction impairs Cav1.2 trafficking, calcium transients, and contractility.

Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Comment in

PMID:
22138472
[PubMed - indexed for MEDLINE]
PMCID:
PMC3306544
Free PMC Article

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