Overexpression of SARAF Ameliorates Pressure Overload-Induced Cardiac Hypertrophy Through Suppressing STIM1-Orai1 in Mice
Overexpression of SARAF Ameliorates Pressure Overload-Induced Cardiac Hypertrophy Through Suppressing STIM1-Orai1 in Mice
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SARAF 的过表达通过抑制 STIM1-Orai1 改善小鼠压力超负荷引起的心脏肥大
DOI：
10.1159/000490036
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发表时间：
2018-01-01
影响因子：
--
通讯作者：
Yang, Dachun
中科院分区：
文献类型：
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作者：
Dai, Fengdan;Zhang, Yan;Yang, Dachun
背景/目的：基质相互作用分子1（stromal interaction molecule 1，STIM 1）和Orai 1的激活参与心肌肥厚的发生。钙池操纵的钙进入相关调节因子（SARAF）是一种STIM 1-Orai 1相互作用的内在抑制因子。因此，我们假设SARAF可以预防心脏肥大。研究方法：将8周龄的雄性C57 BL/6小鼠随机分为假手术组和腹主动脉缩窄手术组，并通过心肌内注射用表达SARAF和GFP的慢病毒（Lenti-SARAF）或单独的GFP（Lenti-GFP）感染。主动脉缩窄术后4周，通过超声心动图和血流动力学测定来评估左心室结构和功能。采用定量PCR和Western blot分别检测SARAF、STIM 1和Orai 1基因和蛋白的表达。结果如下：与假手术组相比，SARAF基因和蛋白表达明显降低，STIM 1和Orai 1表达明显增加。SARAF在心脏中的过表达阻止了STIM 1和Orai 1的上调，重要的是，减弱了主动脉缩窄引起的左心室压力衰减最大速率的降低以及室间隔和左心室后壁厚度、心脏重量/体重比和心肌细胞大小的增加。通过颈动脉检测的血压和左心室收缩功能不受SARAF过表达的影响。此外，SARAF的过度表达也减弱了血管紧张素II诱导的STIM 1和Orai 1的上调以及培养的心肌细胞的肥大。结论：SARAF在心肌中过表达可能通过抑制STIM 1/Orai 1的上调而抑制心肌肥厚。(C)2018作者（S）由S发布。Karger AG，巴塞尔
Background/Aims: Activation of stromal interaction molecule 1 (STIM1) and Orai1 participates in the development of cardiac hypertrophy. Store-operated Ca2+ entry-associated regulatory factor (SARAF) is an intrinsic inhibitor of STIM1-Orai1 interaction. Thus, we hypothesized that SARAF could prevent cardiac hypertrophy. Methods: Male C57BL/6 mice, aged 8 weeks, were randomly divided into sham and abdominal aortic constriction surgery groups and were infected with lentiviruses expressing SARAF and GFP (Lenti-SARAF) or GFP alone (Lenti-GFP) via intramyocardial injection. At 4 weeks after aortic constriction, left ventricular structure and function were assessed by echocardiography and hemodynamic assays. The gene and protein expressions of SARAF, STIM1, and Orai1 were measured by quantitative PCR and Western blot, respectively. Results: Gene and protein expressions of SARAF were significantly decreased, while STIM1 and Orai1 were increased in the heart tissue compared with sham group. Overexpression of SARAF in the heart prevented the upregulation of STIM1 and Orai1, and importantly, attenuated aortic constriction-induced decrease in maximal rate of left ventricular pressure decay and increases in thickness of interventricular septum and left ventricular posterior wall, heart weight/body weight ratio, and size of cardiomyocytes. Blood pressure detected through the carotid artery and left ventricular systolic function were not affected by SARAF overexpression. In addition, overexpression of SARAF also attenuated angiotensin II-induced upregulation of STIM1 and Orai1 and hypertrophy of cultured cardiomyocytes. Conclusion: Overexpression of SARAF in the heart prevents cardiac hypertrophy, probably through suppressing the upregulation of STIM1/Orai1. (C) 2018 The Author(s) Published by S. Karger AG, Basel