MOLECULAR AND PHYSIOLOGICAL ALTERATIONS IN MURINE VENTRICULAR DYSFUNCTION
MOLECULAR AND PHYSIOLOGICAL ALTERATIONS IN MURINE VENTRICULAR DYSFUNCTION
复制标题
DOI：
10.1073/pnas.91.7.2694
复制
发表时间：
1994-03-29
影响因子：
11.1
通讯作者：
CHIEN, KR
中科院分区：
文献类型：
--
作者：
ROCKMAN, HA;ONO, S;CHIEN, KR
本研究报告了通过显微外科入路在肺动脉逐渐收缩后右心室功能障碍的小鼠模型的发展和特征。为了分析体内心室功能，开发了一种x射线造影剂微血管造影技术，可以定量分析正常和压力过载的右心室的心室容量和射血分数。严重的慢性肺动脉束带持续14天，导致右心室扩张和功能障碍，伴有右心房扩大，血管造影显示三尖瓣反流。这些影响取决于血流动力学超载的程度，因为更中度的肺动脉收缩导致肥厚，同时维持右心室功能。随着肺动脉严重收缩，小鼠右心室表现出衰竭的心脏表型，包括心室扩张和功能降低，类似于慢性肺动脉高压期间人类的右心室功能障碍。Northern和免疫印迹分析表明，在两种收缩水平下，磷蛋白mRNA及其相应蛋白的显著下调，而在严重超载时，观察到肌浆网Ca2+- atp酶蛋白的不太明显但显著的抑制，这表明这种模式是心室功能障碍的早期遗传标记。通过将小鼠遗传学与该小鼠模型和体内评估心功能的能力相结合，人们应该能够测试磷蛋白下调和心肌基因程序中其他确定的改变在心力衰竭表型发病中的作用。
The present study reports the development and characterization of a murine model of right ventricular dysfunction following graded constriction in the pulmonary artery via microsurgical approaches. To analyze in vivo ventricular function, a technique of x-rav contrast microangiography was developed to allow the quantitative analysis of ventricular volumes and of ejection fraction in normal and pressure-overloaded right ventricle. Severe, chronic pulmonary arterial banding for 14 days resulted in right ventricular dilatation and dysfunction, associated with right atrial enlargement, and angiographic evidence of tricuspid regurgitation. These effects were dependent on the extent of hemodynamic overload, since more moderate pulmonary arterial constriction resulted in hypertrophy with maintenance of right ventricular function. With severe pulmonary artery constriction, the murine right ventricle displays a failing heart phenotype including chamber dilation with reduced function that resembles right ventricular dysfunction in man during chronic pulmonary arterial hypertension. Northern and immunoblot analyses demonstrate a marked down-regulation of phospholamban mRNA and its corresponding protein with both levels of constriction, while a less pronounced but significant depression of sarcoplasmic reticulum Ca2+-ATPase protein was observed with severe overload, suggesting that this pattern is an early genetic marker of ventricular dysfunction. By coupling mouse genetics with this murine model and the ability to assess cardiac function in vivo, one should be able to test the role of the down-regulation of phospholamban and other defined alterations in the cardiac muscle gene program in the onset of the failing heart phenotype.