LncRNA ZFAS1 as a SERCA2a Inhibitor to Cause Intracellular Ca(2+) Overload and Contractile Dysfunction in a Mouse Model of Myocardial Infarction.
LncRNA ZFAS1 as a SERCA2a Inhibitor to Cause Intracellular Ca(2+) Overload and Contractile Dysfunction in a Mouse Model of Myocardial Infarction.
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LncRNA ZFAS1 作为 SERCA2a 抑制剂导致心肌梗死小鼠模型细胞内 Ca2 超载和收缩功能障碍
DOI：
10.1161/circresaha.117.312117
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发表时间：
2018-05-11
影响因子：
20.1
通讯作者：
Yang B
中科院分区：
文献类型：
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作者：
Zhang Y;Jiao L;Sun L;Li Y;Gao Y;Xu C;Shao Y;Li M;Li C;Lu Y;Pan Z;Xuan L;Zhang Y;Li Q;Yang R;Zhuang Y;Zhang Y;Yang B
补充数字内容可在文本中找到。Ca ~（2+）稳态是心肌收缩功能的重要决定因素，受肌浆网Ca ~（2+）-ATP酶2a（SERCA 2a）的调节。我们以前的研究已经确定ZFAS 1是一种新的急性心肌梗死（MI）的lncRNA生物标志物。评价ZFAS 1对心肌梗死（MI）患者SERCA 2a及相关Ca 2+稳态和心脏收缩功能的影响。在MI小鼠模型和缺氧细胞模型中，ZFAS 1表达在细胞质和肌浆网中显著增加。通过病毒介导的沉默shRNA敲低内源性ZFAS 1可部分消除缺血诱导的收缩功能障碍。ZFAS 1在其他正常小鼠中的过表达产生了与在MI小鼠中观察到的类似的心脏功能损害。此外，在细胞水平上，ZFAS 1过表达减弱了心肌的收缩力。在亚细胞水平，ZFAS 1有害地改变了Ca 2+瞬变，导致心肌细胞内Ca 2+超载。在分子水平上，ZFAS 1被发现直接结合SERCA 2a蛋白并限制其活性，以及抑制其表达。ZFAS 1的作用在敲低该lncRNA时容易逆转。值得注意的是，ZFAS 1基因的一个跨物种保守的序列结构域模拟了全长ZFAS 1的作用。该结构域的突变或该保守区域的反义片段的应用有效地抵消了ZFAS 1的有害作用。ZFAS 1对其他Ca 2+处理调节蛋白没有显著影响。ZFAS 1是一种内源性SERCA 2a抑制剂，通过与SERCA 2a蛋白结合来限制其细胞内水平并抑制其活性，并且是MI中心脏收缩功能受损的贡献者。因此，抗ZFAS 1可能被认为是一种新的治疗策略，用于在心脏病理条件下保护SERCA 2a活性和心脏功能。
Supplemental Digital Content is available in the text. Ca2+ homeostasis—a critical determinant of cardiac contractile function—is critically regulated by SERCA2a (sarcoplasmic reticulum Ca2+-ATPase 2a). Our previous study has identified ZFAS1 as a new lncRNA biomarker of acute myocardial infarction (MI). To evaluate the effects of ZFAS1 on SERCA2a and the associated Ca2+ homeostasis and cardiac contractile function in the setting of MI. ZFAS1 expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia. Knockdown of endogenous ZFAS1 by virus-mediated silencing shRNA partially abrogated the ischemia-induced contractile dysfunction. Overexpression of ZFAS1 in otherwise normal mice created similar impairment of cardiac function as that observed in MI mice. Moreover, at the cellular level, ZFAS1 overexpression weakened the contractility of cardiac muscles. At the subcellular level, ZFAS1 deleteriously altered the Ca2+ transient leading to intracellular Ca2+ overload in cardiomyocytes. At the molecular level, ZFAS1 was found to directly bind SERCA2a protein and to limit its activity, as well as to repress its expression. The effects of ZFAS1 were readily reversible on knockdown of this lncRNA. Notably, a sequence domain of ZFAS1 gene that is conserved across species mimicked the effects of the full-length ZFAS1. Mutation of this domain or application of an antisense fragment to this conserved region efficiently canceled out the deleterious actions of ZFAS1. ZFAS1 had no significant effects on other Ca2+-handling regulatory proteins. ZFAS1 is an endogenous SERCA2a inhibitor, acting by binding to SERCA2a protein to limit its intracellular level and inhibit its activity, and a contributor to the impairment of cardiac contractile function in MI. Therefore, anti-ZFAS1 might be considered as a new therapeutic strategy for preserving SERCA2a activity and cardiac function under pathological conditions of the heart.
影响因子：
3.7
作者：
Faria Tde O;Costa GP;Almenara CC;Angeli JK;Vassallo DV;Stefanon I;Vassallo PF
通讯作者：
Vassallo PF
DOI：
10.5455/aim.2016.24.332-337
发表时间：
2016-10
期刊：
Acta informatica medica : AIM : journal of the Society for Medical Informatics of Bosnia & Herzegovina : casopis Drustva za medicinsku informatiku BiH
影响因子：
--
作者：
Raharjo SJ;Kikuchi T
通讯作者：
Kikuchi T