Increased SR Ca2+ cycling contributes to improved contractile performance in SERCA2a-overexpres sing transgenic rats
Increased SR Ca2+ cycling contributes to improved contractile performance in SERCA2a-overexpres sing transgenic rats
复制标题
DOI：
10.1016/j.cardiores.2005.05.006
复制
发表时间：
2005-09-01
影响因子：
10.8
通讯作者：
Pieske, B
中科院分区：
文献类型：
--
作者：
Maier, LS;Wahl-Schott, C;Pieske, B
目的：心力衰竭与肌浆网（SR）Ca2+-ATP酶（SERCA2a）功能降低有关，但肌膜Na+/Ca2+交换器（NCX）功能增强，导致SR Ca2+含量降低和收缩力频率增强功能丧失。我们报道了转基因大鼠心脏 (TG) 中 SERCA2a 的过度表达导致收缩性改善。然而，尚不清楚 TG 是否因频率依赖性改善 SR Ca2+ 处理而改善收缩性。 方法：因此，我们在生理条件（37 摄氏度，刺激率 < 8 Hz）下对 TG (n=35) 与野生型 (WT) 对照大鼠 (n=39) 进行了表征。测量离体肌肉的抽搐力、细胞内 Ca2+ 瞬变 ([Ca2+](i)) 和 SR Ca2+ 含量。在分离的心肌细胞中研究了通过 L 型 Ca2+ 通道 (LTCC) 和反向模式 NCX (I-Na/Ca) 的跨肌膜 Ca2+ 流入 (I-Ca) 对 Ca2+ 循环的贡献。结果：随着频率的增加，TG 肌肉中的力量增加了 168 +/- 35% (8 Hz; P < 0.05)，SR Ca2+ 含量最大增加了 118 +/- 31% (4 Hz; P < 0.05)。 P<0.05）。在 WT 中，存在平坦的力-频率响应，SR Ca2+ 含量没有变化。 TG 与 WT 中的每个频率下，力的弛豫参数和 [Ca2+](i) 衰减均加速了约 10%。在较长的休息间隔（< 240 秒）下，TG 中的力和 SR Ca2+ 含量显着增加。因此，在肌细胞中测量的绝对 SR Ca2+ 含量增加了类似于 TG 中的 2 倍。 TG 与 WT 相比，通过 I-Ca（0 mV - 10.2 +/- 1.1 对比 -16.9 +/- 1.3 pA/pF）和 I-Na/Ca（0.17 +/- 0.02 对比 0.46 +/- 0.05 pA/pF）估计的跨肌膜 Ca2+ 通量降低（P < 0.05），而 NCX 和 LTCC 蛋白结论：总之，SERCA2a 过表达由于 SR Ca2+ 负荷增加而以频率依赖性方式改善收缩性，而跨肌膜 Ca2+ 通量减少。 (c) 2005 年欧洲心脏病学会。由 Elsevier B.V. 出版。保留所有权利。
Objective: Heart failure is associated with reduced function of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) but increased function of sarcolemmal Na+/Ca2+ exchanger (NCX), leading to decreased SR Ca2+ content and loss of frequency-potentiation of contractile force. We reported that SERCA2a-overexpression in transgenic rat hearts (TG) results in improved contractility. However, it was not clear whether TG have improved contractility due to frequency-dependent improved SR Ca2+ handling.Methods: Therefore, we characterized TG (n=35) vs. wild-type (WT) control rats (n=39) under physiological conditions (37 degrees C, stimulation rate < 8 Hz). Twitch force, intracellular Ca2+ transients ([Ca2+](i)), and SR Ca2+ content were measured in isolated muscles. The contribution of transsarcolemmal Ca2+ influx (I-Ca) through L-type Ca2+ channels (LTCC) and reverse mode NCX (I-Na/Ca) to Ca2+ cycling were studied in isolated myocytes.Results: With increasing frequency, force increased in TG muscles by 168 +/- 35% (8 Hz; P < 0.05) and SR Ca2+ content increased by maximally 118 +/- 31% (4 Hz; P < 0.05). In WT, there was a flat force-frequency response without changes in SR Ca2+ content. Relaxation parameters of force and [Ca2+](i) decay were accelerated at each frequency in TG vs. WT by similar to 10%. At prolonged rest intervals (< 240 s), force and SR Ca2+ content increased significantly more in TG. Consequently, absolute SR Ca2+ content measured in myocytes was increased similar to 2-fold in TG. Transsarcolemmal Ca2+ fluxes estimated by I-Ca (at 0 mV - 10.2 +/- 1.1 vs. -16.9 +/- 1.3 pA/pF) and I-Na/Ca (0.17 +/- 0.02 vs. 0.46 +/- 0.05 pA/pF) were decreased in TG vs. WT (P < 0.05), whereas NCX and LTCC protein expression was only slightly reduced (P=n.s.).Conclusion: In summary, SERCA2a-overexpression improved contractility in a frequency-dependent way due to increased SR Ca2+ loading whereas transsarcolemmal Ca2+ fluxes were decreased. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.