Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice
Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice
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DOI：
10.1093/cvr/cvp016
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发表时间：
2009-04-01
影响因子：
10.8
通讯作者：
Szczesna-Cordary, Danuta
中科院分区：
文献类型：
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作者：
Abraham, Theodore P.;Jones, Michelle;Szczesna-Cordary, Danuta
心室肌球蛋白调节轻链 (RLC) 中的几种突变已被确定可导致家族性肥厚型心肌病 (FHC)。基于我们之前的细胞研究结果显示，转基因 Tg-R58Q 和 Tg-N47K 小鼠的电刺激完整乳头肌纤维中存在延迟的钙瞬变，此外，Tg-R58Q 纤维中的力瞬变时间延长，我们假设与 R58Q 突变相关的恶性 FHC 表型最有可能与舒张功能障碍相关。超声心动图显示的心脏形态和体内血流动力学以及离体心脏功能在转基因（Tg）突变小鼠中评估了灌注工作心脏。在从 Tg 小鼠心脏分离的肌原纤维中测定了 ATPase-pCa 关系。此外，在 Tg 小鼠的快速冷冻心室样本中检查了两种突变对 RLC 磷酸化的影响。值得注意的是，在 Tg-R58Q 和 Tg-N47K 小鼠的分离灌注工作心脏中观察到心功能下降。然而，超声心动图检查显示仅 Tg-R58Q 心肌的舒张期传输速度和减速时间发生显着变化。同样，仅在 Tg-R58Q 小鼠的肌原纤维中观察到 Ca2+ 敏感性、协同性的变化以及低 [Ca2+] 时 ATP 酶活性水平的升高。此外，R58Q 突变而非 N47K 导致 Tg 心室中 RLC 磷酸化降低。我们的结果表明，N47K 和 R58Q 突变可能通过相似的机制起作用，导致功能受损的心肌代偿性肥大，但恶性 R58Q 表型很可能与心脏性能的更严重改变相关，表现为舒张受损和整体舒张功能障碍。在分子水平上，我们认为，通过减少 RLC 的磷酸化，R58Q 突变降低了肌球蛋白跨桥的动力学，导致肌丝钙敏感性增加和细胞内 Ca2+ 稳态的整体变化。
Several mutations in the ventricular myosin regulatory light chain (RLC) were identified to cause familial hypertrophic cardiomyopathy (FHC). Based on our previous cellular findings showing delayed calcium transients in electrically stimulated intact papillary muscle fibres from transgenic Tg-R58Q and Tg-N47K mice and, in addition, prolonged force transients in Tg-R58Q fibres, we hypothesized that the malignant FHC phenotype associated with the R58Q mutation is most likely related to diastolic dysfunction.Cardiac morphology and in vivo haemodynamics by echocardiography as well as cardiac function in isolated perfused working hearts were assessed in transgenic (Tg) mutant mice. The ATPase-pCa relationship was determined in myofibrils isolated from Tg mouse hearts. In addition, the effect of both mutations on RLC phosphorylation was examined in rapidly frozen ventricular samples from Tg mice. Significantly, decreased cardiac function was observed in isolated perfused working hearts from both Tg-R58Q and Tg-N47K mice. However, echocardiographic examination showed significant alterations in diastolic transmitral velocities and deceleration time only in Tg-R58Q myocardium. Likewise, changes in Ca2+ sensitivity, cooperativity, and an elevated level of ATPase activity at low [Ca2+] were only observed in myofibrils from Tg-R58Q mice. In addition, the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg ventricles.Our results suggest that the N47K and R58Q mutations may act through similar mechanisms, leading to compensatory hypertrophy of the functionally compromised myocardium, but the malignant R58Q phenotype is most likely associated with more severe alterations in cardiac performance manifested as impaired relaxation and global diastolic dysfunction. At the molecular level, we suggest that by reducing the phosphorylation of RLC, the R58Q mutation decreases the kinetics of myosin cross-bridges, leading to an increased myofilament calcium sensitivity and to overall changes in intracellular Ca2+ homeostasis.