Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1

Uwe Kirchhefer, Joachim Neumann, Hideo A. Baba, Frank Begrow, Yvonne M. Kobayashi, Uta Reinke, Wilhelm Schmitz, Larry Jones

Research output: Contribution to journalArticle

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Abstract

Triadin 1 is a major transmembrane protein in cardiac junctional sarcoplasmic reticulum (SR), which forms a quaternary complex with the ryanodine receptor (Ca2+ release channel), junctin, and calsequestrin. To better understand the role of triadin 1 in excitation-contraction coupling in the heart, we generated transgenic mice with targeted overexpression of triadin 1 to mouse atrium and ventricle, employing the α-myosin heavy chain promoter to drive protein expression. The protein was overexpressed 5-fold in mouse ventricles, and overexpression was accompanied by cardiac hypertrophy. The levels of two other junctional SR proteins, the ryanodine receptor and junctin, were reduced by 55% and 73%, respectively, in association with triadin 1 overexpression, whereas the levels of calsequestrin, the Ca2+-binding protein of junctional SR, and of phospholamban and SERCA2a, Ca2+-handling proteins of the free SR, were unchanged. Cardiac myocytes from triadin 1-overexpressing mice exhibited depressed contractility; Ca2+ transients decayed at a slower rate, and cell shortening and relengthening were diminished. The extent of depression of cell shortening of triadin 1-overexpressing cardiomyocytes was rate-dependent, being more depressed under low stimulation frequencies (0.5 Hz), but reaching comparable levels at higher frequencies of stimulation (5 Hz). Spontaneously beating, isolated work-performing heart preparations overexpressing triadin 1 also relaxed at a slower rate than control hearts, and failed to adapt to increased afterload appropriately. The fast time inactivation constant, τ1, of the L-type Ca2+ channel was prolonged in transgenic cardiomyocytes. Our results provide evidence for the coordinated regulation of junctional SR protein expression in heart independent of free SR protein expression, and furthermore suggest an important role for triadin 1 in regulating the contractile properties of the heart during excitation-contraction coupling.

Original languageEnglish
Pages (from-to)4142-4149
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number6
DOIs
StatePublished - Feb 9 2001

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Cardiomegaly
Transgenic Mice
Sarcoplasmic Reticulum
Calsequestrin
Cardiac Myocytes
Proteins
Excitation Contraction Coupling
Ryanodine Receptor Calcium Release Channel
Myosin Heavy Chains
triadin
Carrier Proteins
Heart Rate

ASJC Scopus subject areas

  • Biochemistry

Cite this

Kirchhefer, U., Neumann, J., Baba, H. A., Begrow, F., Kobayashi, Y. M., Reinke, U., ... Jones, L. (2001). Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1. Journal of Biological Chemistry, 276(6), 4142-4149. https://doi.org/10.1074/jbc.M006443200

Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1. / Kirchhefer, Uwe; Neumann, Joachim; Baba, Hideo A.; Begrow, Frank; Kobayashi, Yvonne M.; Reinke, Uta; Schmitz, Wilhelm; Jones, Larry.

In: Journal of Biological Chemistry, Vol. 276, No. 6, 09.02.2001, p. 4142-4149.

Research output: Contribution to journalArticle

Kirchhefer, U, Neumann, J, Baba, HA, Begrow, F, Kobayashi, YM, Reinke, U, Schmitz, W & Jones, L 2001, 'Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1', Journal of Biological Chemistry, vol. 276, no. 6, pp. 4142-4149. https://doi.org/10.1074/jbc.M006443200
Kirchhefer U, Neumann J, Baba HA, Begrow F, Kobayashi YM, Reinke U et al. Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1. Journal of Biological Chemistry. 2001 Feb 9;276(6):4142-4149. https://doi.org/10.1074/jbc.M006443200
Kirchhefer, Uwe ; Neumann, Joachim ; Baba, Hideo A. ; Begrow, Frank ; Kobayashi, Yvonne M. ; Reinke, Uta ; Schmitz, Wilhelm ; Jones, Larry. / Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 6. pp. 4142-4149.
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