TY - JOUR
T1 - Impaired relaxation in transgenic mice overexpressing junctin
AU - Kirchhefer, Uwe
AU - Neumann, Joachim
AU - Bers, Donald M
AU - Buchwalow, Igor B.
AU - Fabritz, Larissa
AU - Hanske, Gabriela
AU - Justus, Isabel
AU - Riemann, Burkhard
AU - Schmitz, Wilhelm
AU - Jones, Larry R.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - 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.
AB - 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.
KW - Calcium (cellular)
KW - Contractile function
KW - E-contraction coupling
KW - Hypertrophy
KW - SR (function)
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U2 - 10.1016/S0008-6363(03)00432-2
DO - 10.1016/S0008-6363(03)00432-2
M3 - Article
C2 - 12909320
AN - SCOPUS:10744228510
VL - 59
SP - 369
EP - 379
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 2
ER -