From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S., M.L., C.L., Y. Lu, Z.P., L.X., Yiyuan Zhang, Q.L., R.Y., Y. Zhuang, Yong Zhang, B.Y.).
From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S., M.L., C.L., Y. Lu, Z.P., L.X., Yiyuan Zhang, Q.L., R.Y., Y. Zhuang, Yong Zhang, B.Y.)
Circ Res. 2018 May 11;122(10):1354-1368. doi: 10.1161/CIRCRESAHA.117.312117. Epub 2018 Feb 23.
Ca homeostasis-a critical determinant of cardiac contractile function-is critically regulated by SERCA2a (sarcoplasmic reticulum Ca-ATPase 2a). Our previous study has identified as a new lncRNA biomarker of acute myocardial infarction (MI).
To evaluate the effects of on SERCA2a and the associated Ca homeostasis and cardiac contractile function in the setting of MI.
expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia. Knockdown of endogenous by virus-mediated silencing shRNA partially abrogated the ischemia-induced contractile dysfunction. Overexpression of in otherwise normal mice created similar impairment of cardiac function as that observed in MI mice. Moreover, at the cellular level, overexpression weakened the contractility of cardiac muscles. At the subcellular level, deleteriously altered the Ca transient leading to intracellular Ca overload in cardiomyocytes. At the molecular level, was found to directly bind SERCA2a protein and to limit its activity, as well as to repress its expression. The effects of were readily reversible on knockdown of this lncRNA. Notably, a sequence domain of gene that is conserved across species mimicked the effects of the full-length . Mutation of this domain or application of an antisense fragment to this conserved region efficiently canceled out the deleterious actions of . had no significant effects on other Ca-handling regulatory proteins.
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- might be considered as a new therapeutic strategy for preserving SERCA2a activity and cardiac function under pathological conditions of the heart.
钙稳态是心肌收缩功能的关键决定因素，受 SERCA2a（肌浆网 Ca-ATP 酶 2a）的严格调节。我们之前的研究已经确定 是急性心肌梗死（MI）的新 lncRNA 生物标志物。
评估 在 MI 情况下对 SERCA2a 以及相关钙稳态和心肌收缩功能的影响。
在 MI 模型和缺氧细胞模型中， 在内质网和肌浆网中的表达均显著增加。病毒介导的沉默 shRNA 对内源性 的敲低部分消除了缺血诱导的收缩功能障碍。在其他方面正常的小鼠中过表达 会导致类似的心脏功能损害，就像在 MI 小鼠中观察到的那样。此外，在细胞水平上， 过表达削弱了心肌的收缩力。在亚细胞水平上， 改变了 Ca 瞬变，导致心肌细胞内 Ca 超载。在分子水平上，发现 直接与 SERCA2a 蛋白结合并限制其活性，同时抑制其表达。这种 lncRNA 的敲低很容易逆转这些作用。值得注意的是，在跨物种中保守的 基因的一个序列结构域模拟了全长 的作用。该保守区域的该结构域突变或应用反义片段可有效地消除 的有害作用。 对其他 Ca 处理调节蛋白没有显著影响。
是一种内源性 SERCA2a 抑制剂，通过与 SERCA2a 蛋白结合来限制其细胞内水平并抑制其活性，是 MI 中心脏收缩功能障碍的一个促成因素。因此，抗 可能被认为是在心脏病理条件下保持 SERCA2a 活性和心脏功能的新治疗策略。
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