A knock-in mouse model of N-terminal R420W mutation of cardiac ryanodine receptor exhibits arrhythmogenesis with abnormal calcium dynamics in cardiomyocytes

作者：Okudaira Noriyuki; Kuwahara Masayoshi; Hirata Yutaka; Oku Yoshitaka; Nishio Hajime^*

来源：Biochemical and Biophysical Research Communications, 2014, 452(3): 665-668.

DOI：10.1016/j.bbrc.2014.08.132

• Arrhythmia
• Model mouse
• Sudden death
• Calcium

Cardiac ryanodine receptor gene (RyR2) mutations cause fatal arrhythmogenic diseases such as catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular cardiomyopathy. The N-terminal region of RyR2 is one of the hot spots for mutations. In this study, we investigated cardiac phenotypes of a knock-in mouse model carrying R420W mutation of RyR2. The N-terminal R420W mutation has already been found in juvenile sudden death cadavers of unrelated families. The depolarization-induced Ca2+ transient amplitude was significantly lower in cardiomyocytes from RyR2(R420W/R420W) mice compared with wild-type mice. The time to peak of the Ca2+ transient was significantly increased in RyR2(R420W/R420W) mice. Furthermore, the prolonged decay time from the peak of the Ca2+ transient was detected in RyR2(R420W/R420W) mice. ECG telemetry revealed that various types of arrhythmias were induced in RyR2(R420W/R420W) mice in response to administration of caffeine and adrenaline. The mutant mice showed high occurrences of arrhythmias in response to heart stimulants compared with wild-type mice. These findings suggest that R420W mutation impairs depolarization-induced Ca2+ oscillation in cardiomyocytes, which possibly results in sudden death due to stress-induced arrhythmias.

• 出版日期2014-9-26