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

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.

Pubmed ID: 22138472

Authors

  • Hong TT
  • Smyth JW
  • Chu KY
  • Vogan JM
  • Fong TS
  • Jensen BC
  • Fang K
  • Halushka MK
  • Russell SD
  • Colecraft H
  • Hoopes CW
  • Ocorr K
  • Chi NC
  • Shaw RM

Journal

Heart rhythm : the official journal of the Heart Rhythm Society

Publication Data

May 23, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: K08 HL096836
  • Agency: NHLBI NIH HHS, Id: K99 HL109075
  • Agency: NHLBI NIH HHS, Id: R00 HL109075
  • Agency: NHLBI NIH HHS, Id: R01 HL094414
  • Agency: NHLBI NIH HHS, Id: R01 HL094414-01A1
  • Agency: NHLBI NIH HHS, Id: R01 HL094414-02
  • Agency: NHLBI NIH HHS, Id: R01 HL094414-03
  • Agency: NHLBI NIH HHS, Id: R01 HL094414-04
  • Agency: NHLBI NIH HHS, Id: R01 HL104239

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Animals
  • Calcium
  • Calcium Channels, L-Type
  • Cell Line
  • Heart Failure
  • Humans
  • Mice
  • Myocytes, Cardiac
  • Nuclear Proteins
  • Patch-Clamp Techniques
  • Protein Transport
  • RNA, Messenger
  • Tumor Suppressor Proteins