Pennock G D, Spooner P H, Summers C E, Litwin S E
Department of Medicine, Southern Arizona Veterans Affairs Health Care System and University of Arizona Sarver Heart Center, Tucson, Arizona, USA.
J Mol Cell Cardiol. 2000 Nov;32(11):1939-53. doi: 10.1006/jmcc.2000.1225.
Heart failure of diverse causes is associated with abnormalities of sarcoplasmic reticulum (SR) Ca(2+)transport. The purpose of this study was to determine whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (DITPA), prevents abnormal Ca(2+)transport and expression of SR proteins associated with post-infarction heart failure. New Zealand White rabbits were randomly assigned to circumflex artery ligation or sham operation, and to DITPA administration (3.75 mg/kg/day) or no treatment in a two-by-two factorial design. After 3 weeks, echo-Doppler and LV hemodynamic measurements were performed. From ventricular tissue, single myocyte shortening and relaxation were determined, and Ca(2+)transport was measured in homogenates and SR-enriched microsomes. Levels of mRNA and protein content were determined for the SR Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), cardiac ryanodine receptor (RyR-2) and calsequestrin. The administration of DITPA improved LV contraction and relaxation and improved myocyte shortening in infarcted animals. The improvements in LV and myocyte function were associated with increases in V(max)for SR Ca(2+)transport in both homogenates and microsomes. Also, DITPA prevented the decrease in LV protein density for SERCA2a, PLB and RyR-2 post-infarction, without measurable changes in mRNA levels. The thyroid hormone analogue, DITPA, improves LV, myocyte and SR function in infarcted hearts and prevents the downregulation of SR proteins associated with post-infarction heart failure. The specific effects of DITPA on post-infarction SR Ca(2+)transport and the expression of SR proteins make this compound a potentially useful therapeutic agent for LV systolic and/or diastolic dysfunction.
多种病因导致的心力衰竭与肌浆网（SR）钙（Ca2+）转运异常有关。本研究的目的是确定甲状腺激素类似物3,5 - 二碘甲状腺丙酸（DITPA）是否能预防与心肌梗死后心力衰竭相关的异常Ca2+转运及SR蛋白表达。将新西兰白兔随机分为两组，一组进行冠状动脉回旋支结扎术，另一组进行假手术，并采用二乘二析因设计，分别给予DITPA（3.75毫克/千克/天）或不进行治疗。3周后，进行超声多普勒和左心室血流动力学测量。从心室组织中，测定单个心肌细胞的收缩和舒张情况，并在匀浆和富含SR的微粒体中测量Ca2+转运。测定SR钙ATP酶（SERCA2a）、受磷蛋白（PLB）、心脏雷诺丁受体（RyR - 2）和肌集钙蛋白的mRNA水平和蛋白含量。给予DITPA可改善梗死动物的左心室收缩和舒张功能，并改善心肌细胞缩短。左心室和心肌细胞功能的改善与匀浆和微粒体中SR Ca2+转运的Vmax增加有关。此外，DITPA可预防心肌梗死后左心室SERCA2a、PLB和RyR - 2蛋白密度的降低，而mRNA水平无明显变化。甲状腺激素类似物DITPA可改善梗死心脏的左心室、心肌细胞和SR功能，并预防与心肌梗死后心力衰竭相关的SR蛋白下调。DITPA对心肌梗死后SR Ca2+转运和SR蛋白表达的特异性作用使该化合物成为治疗左心室收缩和/或舒张功能障碍的潜在有用药物。
