Downregulated FKBP12.6 expression and upregulated endothelin signaling contribute to elevated diastolic calcium and arrhythmogenesis in rat cardiomyopathy produced by L-thyroxin

被引：23

作者：

Zhang, Yuan ^{[1
]}

Huang, Zhi-Jiang ^{[1
]}

Dai, De-Zai ^{[1
]}

Feng, Yu ^{[1
]}

Na, Tao ^{[1
]}

Tang, Xiao-Yun ^{[1
]}

Dai, Yin ^{[1
]}

机构：

[1] China Pharmaceut Univ, Res Div Pharmacol, Nanjing 210009, Peoples R China

来源：

INTERNATIONAL JOURNAL OF CARDIOLOGY | 2008年 / 130卷 / 03期

关键词：

Ryanodine receptor 2 (RyR2); FKBP12.6; Cardiac arrhythmias; Endothelin receptor antagonists; Calcium transients;

D O I：

10.1016/j.ijcard.2008.05.018

中图分类号：

R5 [内科学];

学科分类号：

1002 [临床医学]; 100201 [内科学];

摘要：

Background: 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 Ca2+ levels due to dissociation (downregulation) of FKBP12.6 and upregulation of endothelin (ET-1) signaling pathway. Methods: 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. Results: Cardiomyopathy induced by L-thyroxin resulted in an 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 Ca2+ 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. Conclusion: Increased susceptibility to VF in L-thyroxin-induced cardiomyopathy is related to increase in diastolic Ca2+ levels, resulting from downregulated FKBP12.6 and upregulated ET system. ET antagonism might be useful in settings of FKBP12.6 dissociation. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

引用

页码：463 / 471

页数：9

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