Cappelli V, Moggio R, Monti E, Paracchini L, Piccinini F, Reggiani C
Institute of Human Physiology, University of Pavia, Italy.
J Mol Cell Cardiol. 1989 Jan;21(1):93-101. doi: 10.1016/0022-2828(89)91497-1.
The aim of this study was to determine whether variations of isomyosin expression occurred during doxorubicin-induced cardiomyopathy. A suitable experimental model in which pure delayed cardiotoxic effects could be easily studied was adopted. Young adult female Sprague Dawley rats received 9 mg/kg of doxorubicin (DXR) i.v. divided into three subdoses of 3 mg/kg every third day. Control animals received equal volumes of saline. The animals were examined 9 weeks after treatment. At this time the animals treated with DXR showed ECG alterations, reduction of body weight and a marked decrease of both atrial and ventricular mass, but were still fully hemodynamically compensated. Loss of myofibrillar material could be documented by the reduced recovery of myofibril and myosin. The contractile response of papillary muscles isolated from the right ventricle of treated animals was markedly impaired. Ca-Mg-activated and Mg-activated myofibrillar ATPase activity and Ca-activated myosin ATPase activity were determined on ventricular myocardium of control and treated animals. Both myofibrillar and myosin ATPase activities were found to be significantly reduced. Pyrophosphate gel electrophoresis of purified myosin was carried out. The isomyosin pattern of DXR-treated animals showed a pronounced shift towards V3, the percent of alpha heavy chains being 54.6% in treated rats (80.5% in control rats). This isomyosin shift can explain the reduced myofibrillar and myosin ATPase activity found in treated animals.
本研究的目的是确定在阿霉素诱导的心肌病过程中是否发生了异肌球蛋白表达的变化。采用了一种合适的实验模型，在该模型中可以轻松研究单纯的延迟心脏毒性作用。年轻成年雌性Sprague Dawley大鼠静脉注射9 mg/kg阿霉素（DXR），每三天分三次注射，每次3 mg/kg。对照动物注射等量的生理盐水。在治疗9周后对动物进行检查。此时，接受DXR治疗的动物出现心电图改变、体重减轻以及心房和心室重量显著下降，但血流动力学仍完全代偿。肌原纤维和肌球蛋白恢复减少可证明肌原纤维物质的丢失。从治疗动物右心室分离的乳头肌的收缩反应明显受损。测定了对照动物和治疗动物心室心肌的钙镁激活和镁激活的肌原纤维ATP酶活性以及钙激活的肌球蛋白ATP酶活性。发现肌原纤维和肌球蛋白ATP酶活性均显著降低。对纯化的肌球蛋白进行了焦磷酸凝胶电泳。DXR治疗动物的异肌球蛋白模式显示明显向V3转变，治疗大鼠中α重链的百分比为54.6%（对照大鼠中为80.5%）。这种异肌球蛋白转变可以解释在治疗动物中发现的肌原纤维和肌球蛋白ATP酶活性降低的现象。
