Overexpression of junctate induces cardiac hypertrophy and arrhythmia via altered calcium handling

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• 作者：Chang-Soo Hong ; Soon-Jae Kwon ; Myeong-Chan Cho ; Yong-Geun Kwak ; Ki-Chan Ha ; Bingzhe Hong ; Haiying Li ; Soo-Wan Chae ; Ok Hee Chai ; Chang Ho Song ; Yuhua Li ; Joon-Chul Kim ; Sun-Hee Woo ; So-Young Lee ; Chin
• 关键词：Sarcoplasmic reticulum ; Excitation– ; contraction coupling ; Junctin ; Transgenic mice ; Protein kinase A ; Compartmentalization
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2008
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：April 2008
• 卷：44
• 期：4
• 页码：672-682
• 文件大小：1954 K

摘要

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.