Enhanced calreticulin expression promotes calcium-dependent apoptosis in postnatal cardiomyocytes.
Calreticulin (CRT) is one of the major Ca2+ binding chaperone proteins of the endoplasmic reticulum (ER) and an unusual luminal ER protein. Postnatally elevated expression of CRT leads to impaired development of the cardiac conductive system and may be responsible for the pathology of complete heart block. In this study, the molecular mechanisms that affect Ca2+-dependent signal cascades were investigated using CRT-overexpressing cardiomyocytes. In particular, we asked whether calreticulin plays a critical role in the activation of Ca2+-dependent apoptosis. In the cells overexpressing CRT, the intracellular calcium concentration was significantly increased and the activity of PKC and level of SECAR2a mRNA were reduced. Phosphorylation of Akt and ERKs decreased compared to control. In addition the activity of the anti-apoptotic factor, Bcl-2, was decreased and the activities of pro-apoptotic factor, Bax, p53 and caspase 8 were increased, leading to a dramatic augmentation of caspase 3 activity. Our results suggest that enhanced CRT expression in mature cardiomyocytes disrupts intracellular calcium regulation, leading to calcium-dependent apoptosis.
Lim
Soyeon
S
Cardiovascular Research Institute, Cardiology Division, Department of Internal Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Chang
Woochul
W
Lee
Byoung Kwon
BK
Song
Heesang
H
Hong
Ja Hyun
JH
Lee
Sunju
S
Song
Byeong-Wook
BW
Kim
Hye-Jung
HJ
Cha
Min-Ji
MJ
Jang
Yangsoo
Y
Chung
Namsik
N
Choi
Soon-Yong
SY
Hwang
Ki-Chul
KC
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D037282:Calreticulin / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D006321:Heart / Q000196:embryology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D037282:Calreticulin; D002118:Calcium