Olson Richard D, Gambliel Hervé A, Vestal Robert E, Shadle Susan E, Charlier Henry A, Cusack Barry J
Pharmacology and Gerontology Research Unit, Veteran's Affairs Medical Center, 500 W. Fort St., Boise, ID 83702, USA.
Cardiovasc Toxicol. 2005;5(3):269-83. doi: 10.1385/ct:5:3:269.
Utilizing a model of chronic doxorubicin cardiomyopathy, this study examines the relationship between changes in expression and function of calcium handling proteins and contractile dysfunction. A possible mechanism to account for this relationship is suggested. New Zealand white rabbits were injected with either doxorubicin (1 mg/kg, twice weekly for 8 wk) or 0.9% NaCl. Gene transcript, protein levels, and the function of several proteins from the left ventricle were assessed. Protein levels of sarcoplasmic reticulum (SR) Ca2+ transporting ATPase (SERCA2a and b), Ca2+ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [3H]-ryanodine binding (B(max)) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor alpha2 subunit, and SR Ca2+ loading rates were not decreased. However, only protein levels of SERCA2 and RYR2, mRNA levels of RYR2, and Bmax of RYR2 significantly regressed with left-ventricular fractional shortening. Analysis of contractile function of atrial preparations isolated from doxorubicin-treated rabbits revealed that doxorubicin diminished contractility (dF/dt) of rest-potentiated contractions consistent with SR dysfunction. Serum concentrations of free triiodothyronine (T3) decreased in doxorubicin-treated rabbits. Our results suggest that chronic doxorubicin administration in the rabbit causes a SR-dependent contractile dysfunction that may result, in part, from decreased T3.
本研究利用慢性阿霉素心肌病模型，探讨钙处理蛋白表达和功能变化与收缩功能障碍之间的关系，并提出了一种解释这种关系的可能机制。将新西兰白兔分为两组，分别注射阿霉素（1mg/kg，每周两次，共8周）或0.9%氯化钠。评估左心室几种蛋白的基因转录、蛋白水平及功能。阿霉素处理组家兔的肌浆网（SR）Ca2+转运ATP酶（SERCA2a和b）、Ca2+释放通道（RYR2）、肌集钙蛋白、钠钙交换体的蛋白水平，RYR2的mRNA水平以及[3H]-ryanodine与RYR2的结合（B(max)）均显著降低；受磷蛋白、二氢吡啶受体α2亚基的蛋白水平及SR Ca2+负载率未降低。然而，只有SERCA2和RYR2的蛋白水平、RYR2的mRNA水平以及RYR2的Bmax与左心室缩短分数显著相关。对阿霉素处理组家兔分离的心房肌收缩功能分析显示，阿霉素降低了静息增强收缩的收缩力（dF/dt），这与SR功能障碍一致。阿霉素处理组家兔血清游离三碘甲状腺原氨酸（T3）浓度降低。我们的结果表明，兔长期给予阿霉素会导致SR依赖性收缩功能障碍，这可能部分是由于T3降低所致。
