Differential responses of the right ventricle to abnormal loading conditions in mice: pressure vs. volume load
Differential responses of the right ventricle to abnormal loading conditions in mice: pressure vs. volume load
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DOI：
10.1093/eurjhf/hfr134
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发表时间：
2011-12-01
影响因子：
18.2
通讯作者：
Berger, Rolf M. F.
中科院分区：
文献类型：
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作者：
Bartelds, Beatrijs;Borgdorff, Marinus A.;Berger, Rolf M. F.
目的右心室功能障碍是先天性心脏病长期发病率和死亡率的主要决定因素。右心室（RV）在基因上与左心室（LV）不同，但这是否会影响细胞对异常负荷条件的反应尚不清楚。在左室，钙调磷酸酶活化是病理性肥大的主要决定因素，也是治疗策略的重要靶点。我们在小鼠压力和体积负荷模型中研究了RV的功能和分子适应性，重点研究了钙调磷酸酶的激活。方法和结果小鼠分别接受肺动脉束带（PAB）、主动脉-腔静脉分流术（shunt）和假手术（Control）。四周后，通过心脏磁共振成像、压力测量和自愿笼轮运动对小鼠进行功能评估。牺牲后观察右心室肥厚和钙调磷酸酶活化。右心室压力负荷（PAB）或体积负荷（Shunt）增加的小鼠出现了相似程度的肥大，但表现出不同的功能和分子适应。肺动脉束带增加了调钙调磷酸酶相互作用蛋白1 （MCIP1）的表达，表明钙调磷酸酶被激活，以及β / α -肌球蛋白重链（MHC）的比值。此外，PAB降低运动能力，诱导中度右心室扩张，静息时右心室输出正常。相比之下，分流没有增加MCIP1的表达，只是适度增加β / α - mhc比值。分流不影响运动能力，但增加了静息时的RV体积和输出。结论压力和体积负荷诱导了RV不同的功能和分子适应。这些结果可能对预防成年先天性心脏病患者右心室衰竭的治疗策略产生重要影响。
Aims Right ventricular (RV) dysfunction is a major determinant of long-term morbidity and mortality in congenital heart disease. The right ventricle (RV) is genetically different from the left ventricle (LV), but it is unknown as to whether this has consequences for the cellular responses to abnormal loading conditions. In the LV, calcineurin-activation is a major determinant of pathological hypertrophy and an important target for therapeutic strategies. We studied the functional and molecular adaptation of the RV in mouse models of pressure and volume load, focusing on calcineurin-activation.Methods and results Mice were subjected to pulmonary artery banding (PAB), aorto-caval shunt (Shunt), or sham surgery (Control). Four weeks later, mice were functionally evaluated with cardiac magnetic resonance imaging, pressure measurements, and voluntary cage wheel exercise. Right ventricular hypertrophy and calcineurin-activation were assessed after sacrifice. Mice with increased pressure load (PAB) or volume load (Shunt) of the RV developed similar degrees of hypertrophy, yet revealed different functional and molecular adaptation. Pulmonary artery banding increased expression of Modulatory-Calcineurin-Interacting-Protein 1 (MCIP1), indicating calcineurin-activation, and the ratio of beta/alpha-Myosin Heavy Chain (MHC). In addition, PAB reduced exercise capacity and induced moderate RV dilatation with normal RV output at rest. In contrast, Shunt did not increase MCIP1 expression, and only moderately increased beta/ alpha-MHC ratio. Shunt did not affect exercise capacity, but increased RV volumes and output at rest.Conclusions Pressure and volume load induced different functional and molecular adaptations in the RV. These results may have important consequences for therapeutic strategies to prevent RV failure in the growing population of adults with congenital heart disease.