Changes in STIM Isoforms Expression and Gender-Specific Alterations in Orai Expression in Human Heart Failure
Changes in STIM Isoforms Expression and Gender-Specific Alterations in Orai Expression in Human Heart Failure
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DOI：
10.33549/physiolres.934300
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发表时间：
2019-01-01
影响因子：
2.1
通讯作者：
Matus, M.
中科院分区：
文献类型：
--
作者：
Cendula, R.;Dragun, M.;Matus, M.
钙库操纵性钙内流（SOCE）是调节心脏钙循环的重要机制之一。病理条件下的SOCE改变通过多种信号通路（例如Cn/NFAT和CaMKII/MEF 2）促进心力衰竭和心脏肥大的进展。已经确定了几种介导SOCE的成分，如STIM和奥赖。在动物研究中检测到奥赖和STIM的不同亚型，表现出不同的功能特性。本研究旨在分析STIM和奥赖亚型在人类终末期衰竭心肌中的表达。使用从接受心脏移植的患者的43颗外植心脏和5颗健康供体心脏中分离的左心室样本，通过qRT-PCR测定Orai 1、Orai 2和Orai 3、STIM 1、STIM 2和STIM 2.1的mRNA水平。进一步分析该表达与性别、相关共病、病因、临床数据和生化参数的关系。我们发现，尽管我们没有检测到Orai 2或Orai 3表达的显著变化，但在衰竭心肌中Orai 1表达降低了30%。有趣的是，Orai 1的这种下降具有性别特异性，仅存在于男性中，女性中没有变化。男性的Orai 1/Orai 3比率也显着较低。在健康和衰竭的人类心肌中都检测到新型STIM 2.1亚型。在终末期心力衰竭时，STIM2.1的表达明显降低。衰竭心脏中较低的STIM2.1/STIM 2比率表明从SOCE抑制性STIM2.1同种型转换为刺激性STIM2.2。STIM 1 mRNA水平无显著变化。这些观察到的奥赖和STIM表达的改变与功能性心脏参数、临床或生化患者特征无关。这些结果提供了详细的了解人类衰竭心肌中SOCE调节的改变。Orai 1表达的性别特异性变化可能是雌激素心脏保护作用的一种可能机制。从STIM2.1到STIM2.2的转换表明SOCE的扩增，并可能有助于心脏肥大的发展。
Store-operated calcium entry (SOCE) is one of regulatory mechanisms which regulates Ca2+ cycling in the heart. SOCE alterations in pathological conditions contribute to progression of heart failure and cardiac hypertrophy by multiple signaling pathways such as Cn/NFAT and CaMKII/MEF2. Several components mediating SOCE have been identified, such as STIM and Orai. Different isoforms of both Orai and STIM have been detected in animal studies, exhibiting distinct functional properties. This study is focused on the analysis of STIM and Orai isoforms expression in the end-stage human failing myocardium. Left ventricle samples isolated from 43 explanted hearts from patients undergoing heart transplant and from 5 healthy donor hearts were used to determine the mRNA levels of Orai1, Orai2 and Orai3, STIM1, STIM2 and STIM2.1 by qRT-PCR. The expression was further analyzed for connection with gender, related co-morbidities, pathoetiology, clinical data and biochemical parameters. We show that Orai1 expression is decreased by 30 % in failing myocardium, even though we detected no significant changes in expression of Orai2 or Orai3. Interestingly, this decrease in Orai1 was gender-specific and was present only in men, with no change in women. The ratio Orai1/Orai3 was significantly lower in males as well. The novel STIM2.1 isoform was detected both in healthy and failing human myocardium. In the end-stage heart failure, the expression of STIM2.1 was significantly decreased. The lower ratio of STIM2.1/STIM2 in failing hearts indicates a switch from SOCE-inhibiting STIM2.1 isoform to stimulatory STIM2.2. STIM1 mRNA levels were not significantly changed. These observed alterations in Orai and STIM expression were independent of functional heart parameters, clinical or biochemical patient characteristics. These results provide detailed insight into the alterations of SOCE regulation in human failing myocardium. Gender-specific change in Orai1 expression might represent a possible mechanism of cardioprotective effects of estrogens. The switch from STIM2.1 to STIM2.2 indicates an amplification of SOCE and could contribute to the hypertrophy development in the filing heart.