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

被引:126
作者
Hong, Ting-Ting [1 ]
Smyth, James W. [1 ]
Chu, Kevin Y. [1 ]
Vogan, Jacob M. [1 ]
Fong, Tina S. [1 ]
Jensen, Brian C. [2 ]
Fang, Kun [3 ]
Halushka, Marc K. [4 ]
Russell, Stuart D. [5 ]
Colecraft, Henry [3 ]
Hoopes, Charles W. [6 ]
Ocorr, Karen [7 ]
Chi, Neil C. [8 ]
Shaw, Robin M. [1 ,2 ]
机构
[1] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA
[3] Columbia Univ, Dept Physiol, New York, NY 10027 USA
[4] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA
[5] Johns Hopkins Univ, Dept Med, Baltimore, MD USA
[6] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA
[7] Sanford Burnham Med Res Inst, La Jolla, CA USA
[8] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
Calcium; L-type calcium channel; Trafficking; Cardiomyopathy; Heart failure; Ion channels; Calcium transient; VENTRICULAR MYOCYTES; AMPHIPHYSIN-2; BIN1; CALCIUM-CHANNEL; HEART-FAILURE; T-TUBULES; ANKYRIN-G; EXPRESSION; RECEPTOR; DENSITY; SURFACE;
D O I
10.1016/j.hrthm.2011.11.055
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 read-out 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.
引用
收藏
页码:812 / 820
页数:9
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