Overexpression of junctate induces cardiac hypertrophy and arrhythmia via altered calcium handling.
Junctate-1 is a newly identified integral endoplasmic/sarcoplasmic reticulum Ca2+ binding protein. However, its functional role in the heart is unknown. In the present study, the consequences of constitutively overexpressed junctate in cardiomyocytes were investigated using transgenic (TG) mice overexpressing junctate-1. TG mice (8 weeks old) showed cardiac remodeling such as marked bi-atrial enlargement with intra-atrial thrombus and biventricular hypertrophy. The TG mice also showed bradycardia with atrial fibrillation, reduced amplitude and elongated decay time of Ca2+ transients, increased L-type Ca2+ current and prolonged action potential durations. Time-course study (2-8 weeks) showed an initially reduced SR function due to down-regulation of SERCA2 and calsequestrin followed by sarcolemmal protein expression and cardiac hypertrophy at later age. These sequential changes could well be correlated with the physiological changes. Adrenergic agonist treatment and subsequent biochemical study showed that junctate-1 TG mice (8 weeks old) were under local PKA signaling that could cause increased L-type Ca2+ current and reduced SR function. Junctate-1 in the heart is closely linked to the homeostasis of E-C coupling proteins and a sustained increase of junctate-1 expression leads to a severe cardiac remodeling and arrhythmias.
Hong
Chang-Soo
CS
Department of Biological Science, College of Natural Sciences, Daegu University, Gyeongsan, South Korea.
Kwon
Soon-Jae
SJ
Cho
Myeong-Chan
MC
Kwak
Yong-Geun
YG
Ha
Ki-Chan
KC
Hong
Bingzhe
B
Li
Haiying
H
Chae
Soo-Wan
SW
Chai
Ok Hee
OH
Song
Chang Ho
CH
Li
Yuhua
Y
Kim
Joon-Chul
JC
Woo
Sun-Hee
SH
Lee
So-Young
SY
Lee
Chin Ok
CO
Kim
Do Han
DH
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D001919:Bradycardia / Q000000981:diagnostic imaging / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004594:Electrophysiology; D042541:Intracellular Space / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity; D014463:Ultrasonography; D020257:Ventricular Remodeling
D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C498841:Asph protein, mouse; D006899:Mixed Function Oxygenases; D017868:Cyclic AMP-Dependent Protein Kinases