STIM1 elevation in the heart results in aberrant Ca²⁺ handling and cardiomyopathy.
STIM1 elevation in the heart results in aberrant Ca²⁺ handling and cardiomyopathy.
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DOI：
10.1016/j.yjmcc.2015.07.032
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发表时间：
2015-10
影响因子：
5
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Correll RN;Goonasekera SA;van Berlo JH;Burr AR;Accornero F;Zhang H;Makarewich CA;York AJ;Sargent MA;Chen X;Houser SR;Molkentin JD
基质相互作用分子1（Stromal interaction molecule 1，STIM 1）是一种钙离子传感器，与Orai 1结合，在内质网（ER）钙库耗竭时引发钙离子进入。虽然钙库操纵的钙内流（SOCE）对于维持非兴奋性细胞中ER Ca 2+稳态很重要，但尚不清楚它在心脏中起什么作用，尽管STIM 1在心脏中表达并在疾病期间上调。在这里，我们分析了心脏中STIM 1过表达的转基因小鼠，以模拟已知的这种蛋白质在疾病中的增加。正如预期的那样，STIM 1转基因心肌细胞显示出增强的钙离子进入后存储耗尽和部分共定位与2型ryanodine受体（RyR 2）内的肌浆网（SR），以及周围的肌膜富集。STIM 1转基因小鼠早在6周龄时就表现出心脏性猝死，而存活超过12周龄的小鼠则出现心力衰竭伴肥大、胎儿基因程序诱导、组织病理学和线粒体结构改变、心室功能丧失和肺水肿。与对照组相比，年轻的、症状前的STIM 1转基因小鼠在压力过载刺激或神经体液激动剂输注后表现出增强的病理学。从机制上讲，从STIM 1转基因小鼠分离的心肌细胞显示自发的Ca 2+瞬变，这被SOCE阻断剂SKF-96365阻止，增加L型Ca 2+通道（LTCC）电流，并增强Ca 2+火花频率。此外，STIM 1转基因小鼠的成年心肌细胞显示舒张期Ca 2+和最大瞬时振幅增加，但总SR Ca 2+负荷没有增加。与这种增强的Ca 2+分布相关的是激活的T细胞的心脏核因子（NFAT）和Ca 2 +/钙调蛋白依赖性激酶II（CaMKII）活性的增加。我们得出结论，STIM 1在心脏中具有意想不到的功能，它改变了肌膜和SR之间的通信，导致更大的Ca 2+通量和SR室泄漏。
Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor that partners with Orai1 to elicit Ca2+ entry in response to endoplasmic reticulum (ER) Ca2+ store depletion. While store-operated Ca2+ entry (SOCE) is important for maintaining ER Ca2+ homeostasis in non-excitable cells, it is unclear what role it plays in the heart, although STIM1 is expressed in the heart and upregulated during disease. Here we analyzed transgenic mice with STIM1 overexpression in the heart to model the known increase of this protein in response to disease. As expected, STIM1 transgenic myocytes showed enhanced Ca2+ entry following store depletion and partial co-localization with the type 2 ryanodine receptor (RyR2) within the sarcoplasmic reticulum (SR), as well as enrichment around the sarcolemma. STIM1 transgenic mice exhibited sudden cardiac death as early as 6 weeks of age, while mice surviving past 12 weeks of age developed heart failure with hypertrophy, induction of the fetal gene program, histopathology and mitochondrial structural alterations, loss of ventricular functional performance and pulmonary edema. Younger, pre-symptomatic STIM1 transgenic mice exhibited enhanced pathology following pressure overload stimulation or neurohumoral agonist infusion, compared to controls. Mechanistically, cardiac myocytes isolated from STIM1 transgenic mice displayed spontaneous Ca2+ transients that were prevented by the SOCE blocker SKF-96365, increased L-type Ca2+ channel (LTCC) current, and enhanced Ca2+ spark frequency. Moreover, adult cardiac myocytes from STIM1 transgenic mice showed both increased diastolic Ca2+ and maximal transient amplitude but no increase in total SR Ca2+ load. Associated with this enhanced Ca2+ profile was an increase in cardiac nuclear factor of activated T-cells (NFAT) and Ca2+/calmodulin-dependent kinase II (CaMKII) activity. We conclude that STIM1 has an unexpected function in the heart where it alters communication between the sarcolemma and SR resulting in greater Ca2+ flux and a leaky SR compartment.