Impaired relaxation in transgenic mice overexpressing junctin

Uwe Kirchhefer, Joachim Neumann, Donald M Bers, Igor B. Buchwalow, Larissa Fabritz, Gabriela Hanske, Isabel Justus, Burkhard Riemann, Wilhelm Schmitz, Larry R. Jones

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Abstract

Objective: Junctin is a major transmembrane protein in cardiac junctional sarcoplasmic reticulum, which forms a quaternary complex with the ryanodine receptor (Ca2+ release channel), triadin, and calsequestrin. Methods: To better understand the role of junctin in excitation-contraction coupling in the heart, we generated transgenic mice with targeted overexpression of junctin to mouse heart, using the α-MHC promoter to drive protein expression. Results: The protein was overexpressed 10-fold in mouse ventricles and overexpression was accompanied by cardiac hypertrophy (19%). The levels of two other junctional SR-proteins, the ryanodine receptor and triadin, were reduced by 32% and 23%, respectively. However, [3H]ryanodine binding and the expression levels of calsequestrin, phospholamban and SERCA2a remained unchanged. Cardiomyocytes from junctin-overexpressing mice exhibited impaired relaxation: Ca2+ transients decayed at a slower rate and cell relengthening was prolonged. Isolated electrically stimulated papillary muscles from junctin-overexpressing hearts exhibited prolonged mechanical relaxation, and echocardiographic parameters of relaxation were prolonged in the living transgenic mice. The amplitude of caffeine-induced Ca2+ transients was lower in cardiomyocytes from junctin-overexpressing mice. The inactivation kinetics of L-type Ca2+ channel were prolonged in junctin-overexpressing cardiomyocytes using Ca2+ or Ba2+ as charge carriers. Conclusion: Our data provide evidence that cardiac-specific overexpression of junctin is accompanied by impaired myocardial relaxation with prolonged Ca2+ transient kinetics on the cardiomyocyte level.

Original languageEnglish (US)
Pages (from-to)369-379
Number of pages11
JournalCardiovascular Research
Volume59
Issue number2
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

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Keywords

  • Calcium (cellular)
  • Contractile function
  • E-contraction coupling
  • Hypertrophy
  • SR (function)

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Kirchhefer, U., Neumann, J., Bers, D. M., Buchwalow, I. B., Fabritz, L., Hanske, G., Justus, I., Riemann, B., Schmitz, W., & Jones, L. R. (2003). Impaired relaxation in transgenic mice overexpressing junctin. Cardiovascular Research, 59(2), 369-379. https://doi.org/10.1016/S0008-6363(03)00432-2