Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation
Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation
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DOI：
10.1016/j.hrthm.2008.03.030
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发表时间：
2008-07-01
期刊：
影响因子：
5.5
通讯作者：
Wehrens, Xander H. T.
中科院分区：
文献类型：
--
作者：
Sood, Subeena;Chelu, Mihail G.;Wehrens, Xander H. T.
背景虽然钙稳态的缺陷可能导致心房颤动（AF）的发生，但其潜在的分子机制仍知之甚少。对AF患者的研究表明，肌浆网（SR）钙释放通道的舒张期关闭受损（兰尼碱受体，RyR 2）与RyR 2抑制亚基FKBP12.6水平的降低有关。目的本研究旨在验证FKBP12.6缺陷（-/-）患者SR通过RyR 2的Ca 2+渗漏增加AF倾向的假设。方法同时记录FKBP 12.6-/-小鼠和野生型（WT）小鼠的体表心电图和心内心电图。在注射RyR 2拮抗剂丁卡因（0.5mg/kg）之前和之后进行右心房程序刺激。结果FKBP12.6-/-小鼠心房结构正常，细胞内Ca 2+转运蛋白表达无明显变化。81%的FKBP 12.6-/-小鼠可诱导房颤发作，但WT小鼠仅为7%（P
BACKGROUND Although defective Ca2+ homeostasis may contribute to arrhythmogenesis in atrial fibrillation (AF), the underlying molecular mechanisms remain poorly understood. Studies in patients with AF revealed that impaired diastolic closure of sarcoplasmic reticulum (SR) Ca2+-release channels (ryanodine receptors, RyR2) is associated with reduced levels of the RyR2-inhibitory subunit FKBP12.6.OBJECTIVE The objective of the present study was to test the hypothesis that Ca2+ Leak from the SR through RyR2 increases the propensity for AF in FKBP12.6-deficient (-/-) mice.METHODS Surface electrocardiogram and intracardiac etectrograms were recorded simultaneously in FKBP12.6-/- mice and wild-type (WT) littermates. Right atrial programmed stimulation was performed before and after injection of RyR2 antagonist tetracaine (0.5 mg/kg). Intracellular Ca2+ transients were recorded in atrial myocytes from FKBP12.6-/- and WT mice.RESULTS FKBP12.6-/- mice had structurally normal atria and unaltered expression of key Ca2+-handling proteins. AF episodes were inducible in 81% of FKBP12.6-/-, but in only 7% of WT mice (P