Ca2+ entry mode of Na+/Ca2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction
Ca2+ entry mode of Na+/Ca2+ exchanger as a new therapeutic target for heart failure with preserved ejection fraction
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DOI：
10.1093/eurheartj/ehr106
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发表时间：
2012-06-01
影响因子：
39.3
通讯作者：
Yamamoto, Kazuhiro
中科院分区：
文献类型：
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作者：
Kamimura, Daisuke;Ohtani, Tomohito;Yamamoto, Kazuhiro
左心室（LV）纤维化和硬化在射血分数保留的心力衰竭（HFPEF）的发展中起着至关重要的作用。高血压患者血浆中洋地黄样因子 (DLF) 水平升高，高血压是 HFPEF 的主要潜在心血管疾病。洋地黄样因子抑制 Na/K-ATP 酶的离子泵功能并激活 Na/Ca-2 交换器 (NCX) 的 Ca-2 进入模式。已知洋地黄样因子可促进成纤维细胞中胶原蛋白的产生。本研究的目的是探讨NCX进入模式的药理抑制是否能有效预防左室纤维化和HFPEF的发展。(i)从6周龄起喂食8 NaCl饮食的Dahl盐敏感大鼠作为高血压HFPEF模型。在该模型中，在代偿性肥厚和心力衰竭阶段，DLF 的 24 小时尿液排泄量高于年龄匹配的对照。 (ii) 连续给予哇巴因 14 周，使 SpragueDawley 大鼠出现左心室纤维化，但不影响血压。 (iii) 哇巴因通过细胞外 Ca-2 的进入提高细胞内 Ca-2 浓度，增加 p42/44 丝裂原激活蛋白激酶的磷酸化水平，并增强心脏成纤维细胞中的 H-3-脯氨酸掺入； NCX 进入模式抑制剂 SEA0400 抑制了这些效应。 (iv) 在 HFPEF 模型中，亚降压剂量的 SEA0400 给药可提高存活率，并减轻左室纤维化和硬化。洋地黄样因子和随后激活的 NCX 进入模式可能在高血压 HFPEF 的发生过程中发挥重要作用，阻断 NCX 进入模式可能是治疗这种心力衰竭表型的新策略。
Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na/K-ATPase and activate the Ca-2 entry mode of Na/Ca-2 exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF.(i) Dahl salt-sensitive rats fed 8 NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in SpragueDawley rats. (iii) Ouabain elevated intracellular Ca-2 concentration through the entry of extracellular Ca-2, increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced H-3-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening.Digitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.