Zhang Yuan, Huang Zhi-Jiang, Dai De-Zai, Feng Yu, Na Tao, Tang Xiao-Yun, Dai Yin
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China.
Int J Cardiol. 2008 Nov 28;130(3):463-71. doi: 10.1016/j.ijcard.2008.05.018. Epub 2008 Aug 5.
Dissociation of FKBP12.6 from RyR2 is considered as an important molecular event resulting in calcium leak and an increased risk in arrhythmogenesis. We hypothesized that augmented ventricular fibrillation (VF) on reperfusion of rat cardiomyopathy induced by l-thyroxin may result from elevated diastolic Ca(2+) levels due to dissociation (downregulation) of FKBP12.6 and upregulation of endothelin (ET-1) signaling pathway.
Rats were treated with l-thyroxin (0.4 mg/kg, s.c.) for 10 days. Dajisentan (CPU0213), a dual endothelin receptor antagonist (100 mg/kg p.o.), or propranolol was administered on day 6 to 10. Susceptibility to VF was evaluated on ischemia/reperfusion episode. mRNA expression of FKBP12.6, and ET-1 levels were determined. Calcium transients and FKBP12.6 immunohistochemistry were measured by confocal microscopy in isolated cardiomyocytes from cardiomyopathy.
Cardiomyopathy induced by l-thyroxin resulted in an increased susceptibility to VF on ischemia/reperfusion. Upregulated mRNA expression of RyR2 and PKA in association with downregulated FKBP12.6 expression was found in l-thyroxin-treated rats compared to controls. Calcium transients evoked by field electrical stimulation showed an increase in Ca(2+) by +75% during diastole. An increase in ET-1 (ng/mg protein) (+36.6%) and mRNA abundance of preproET-1 were found in the left ventricle. A decreased mRNA ratio of FKBP12.6 to RyR2 likely reflected dissociation of FKBP12.6 in cardiomyopathy. These changes were normalized by Dajisentan, comparable to propranolol.
Increased susceptibility to VF in l-thyroxin-induced cardiomyopathy is related to increase in diastolic Ca(2+) levels, resulting from downregulated FKBP12.6 and upregulated ET system. ET antagonism might be useful in settings of FKBP12.6 dissociation.
FKBP12.6从兰尼碱受体2（RyR2）解离被认为是导致钙泄漏和心律失常风险增加的重要分子事件。我们推测，l-甲状腺素诱导的大鼠心肌病再灌注时室颤（VF）增加可能是由于FKBP12.6解离（下调）和内皮素（ET-1）信号通路上调导致舒张期Ca²⁺水平升高所致。
大鼠皮下注射l-甲状腺素（0.4mg/kg）10天。在第6至10天给予双重内皮素受体拮抗剂达吉生坦（CPU0213，100mg/kg口服）或普萘洛尔。评估缺血/再灌注时对VF的易感性。测定FKBP12.6的mRNA表达和ET-1水平。通过共聚焦显微镜测量心肌病分离心肌细胞中的钙瞬变和FKBP12.6免疫组化。
l-甲状腺素诱导的心肌病导致缺血/再灌注时对VF的易感性增加。与对照组相比，l-甲状腺素处理的大鼠中发现兰尼碱受体2（RyR2）和蛋白激酶A（PKA）的mRNA表达上调，同时FKBP12.6表达下调。场电刺激诱发的钙瞬变显示舒张期Ca²⁺增加了75%。左心室中ET-1（ng/mg蛋白）增加了36.6%，前内皮素原-1（preproET-1）的mRNA丰度增加。FKBP12.6与RyR2的mRNA比值降低可能反映了心肌病中FKBP12.6的解离。这些变化被达吉生坦归一化，与普萘洛尔相当。
l-甲状腺素诱导的心肌病中对VF的易感性增加与舒张期Ca²⁺水平升高有关，这是由于FKBP12.6下调和ET系统上调所致。ET拮抗在FKBP12.6解离的情况下可能有用。
