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Articles in PresS, published online ahead of print May 30, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00937.2001
Submitted on October 30, 2001
Accepted on May 29, 2002
1 Medicine, Institut fur Pharmakologie und Toxikologie, Munster, Germany
2 Medicine, Gerhard-Domagk-Institut fur Pathologie, Munster, Germany
3 Medicine, Krannert Institute of Cardiology, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: kirchhef{at}uni-muenster.de.
Triadin 1 is a protein in the cardiac junctional sarcoplasmic reticulum (SR) that interacts with the ryanodine receptor, junctin, and calsequestrin, proteins that are all important for Ca2+ release. To better understand the role of triadin 1 in SR-Ca2+ release, we studied the time-dependent expression of SR-proteins and contractility in atria of transgenic mice overexpressing canine cardiac triadin 1 under control of the 
-MHC promoter. The investigations were performed on 3-, 6-, and 18-week old mice. Three-week old transgenic atria exhibited mild hypertrophy (13% increase of atrial weight) and fibrosis (2-fold increase) was detected. Hypertrophy and fibrosis were augmented in 6-week old transgenic mice. Finally, atrial weight was increased by 110% in 18-week old transgenic mice. These atria were characterized by severe fibrosis (11-fold increase) and subcellular disarrangement. The overexpression of triadin 1 was accompanied by time-dependent changes in the protein expression of the ryanodine receptor, junctin, and SERCA2a. Contractility measurements with atrial strips revealed that the force of contraction was already decreased in 3-week old transgenic mice in a frequency-dependent manner. Furthermore, the time to peak tension was prolonged in 6- and 18-week old transgenic atria, whereas the time of relaxation was enhanced in transgenic mice of all ages. The application of 10 mM caffeine led to a positive inotropic effect in transgenic atria of 3-week old mice, whereas 18-week old mice showed a negative inotropic effect. Rest pauses resulted in an increased potentiation of force of contraction after restimulation in 3- and 6-week old and a reduced potentiation of force of contraction in 18-week old transgenic mice. Hence, the overexpression of triadin 1 triggered time-dependent alterations in SR-protein expression, SR-Ca2+ homeostasis and contractility, indicating for the first time an inhibitory function of triadin 1 on SR-Ca2+ release in vivo.
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