Up-regulation of micro-RNA765 in human failing hearts is associated with post-transcriptional regulation of protein phosphatase inhibitor-1 and depressed contractility.
Up-regulation of micro-RNA765 in human failing hearts is associated with post-transcriptional regulation of protein phosphatase inhibitor-1 and depressed contractility.
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人类衰竭心脏中 micro-RNA765 的上调与蛋白磷酸酶抑制剂 1 的转录后调节和收缩力下降有关
DOI：
10.1002/ejhf.323
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发表时间：
2015-08
影响因子：
18.2
通讯作者：
Kranias EG
中科院分区：
文献类型：
--
作者：
Cai WF;Liu GS;Lam CK;Florea S;Qian J;Zhao W;Pritchard T;Haghighi K;Lebeche D;Lu LJ;Deng J;Fan GC;Hajjar RJ;Kranias EG
肌浆网（SR）Ca 2+循环受损和收缩性降低是人类和实验性心力衰竭的标志，部分归因于蛋白磷酸酶1（PP-1）活性增加，与其内源性抑制剂-1的下调相关。在衰竭的心脏中，抑制剂-1的水平和活性降低，有助于关键钙循环蛋白的去磷酸化和失活。因此，我们研究了通过转录后修饰介导抑制剂-1减少的机制。生物信息学显示，17种人类microRNA可能作为抑制剂-1的调节剂。然而，实时PCR分析仅确定了这些microRNA中的一种，miR-765，在人类衰竭心脏中增加，伴随着抑制剂-1水平的降低。miR-765在HEK 293细胞或小鼠心室肌细胞中的表达证实了通过该miR-765与抑制剂-1 mRNA的3′-非翻译区结合来抑制抑制剂-1水平。为了确定miR-765在Ca 2+循环中的功能意义，在成年小鼠心室肌细胞中表达pri-miR-765以及非翻译核苷酸序列（miR-Ctrl）。与miR-Ctrl组相比，miR-765心肌细胞中抑制剂-1表达水平降低，伴随PP-1活性增强，这些反映了收缩力学和Ca 2+瞬变的抑制。抑制作用与受磷蛋白磷酸化和SR Ca 2+负荷的减少有关。这些miR-765负性肌力作用在抑制剂-1缺陷的心肌细胞中被消除，表明其对抑制剂-1的明显特异性。miR-765水平在人类衰竭心脏中增加。这种增加可能通过降低抑制剂-1表达和增强PP-1活性（与SR Ca 2+负荷降低相关）导致心脏功能降低。
Impaired sarcoplasmic reticulum (SR) Ca2+ cycling and depressed contractility, a hallmark of human and experimental heart failure, has been partially attributed to increased protein phosphatase 1 (PP-1) activity, associated with down-regulation of its endogenous inhibitor-1. The levels and activity of inhibitor-1 are reduced in failing hearts, contributing to dephosphorylation and inactivation of key calcium cycling proteins. Therefore, we investigated the mechanisms that mediate decreases in inhibitor-1 by post-transcriptional modification. Bioinformatics revealed that 17 human microRNAs may serve as modulators of inhibitor-1. However, real-time PCR analysis identified only one of these microRNAs, miR-765, as being increased in human failing hearts concomitant with decreased inhibitor-1 levels. Expression of miR-765 in HEK293 cells or mouse ventricular myocytes confirmed suppression of inhibitor-1 levels through binding of this miR-765 to the 3′-untranslated region of inhibitor-1 mRNA. To determine the functional significance of miR-765 in Ca2+ cycling, pri-miR-765 as well as a non-translated nucleotide sequence (miR-Ctrl) were expressed in adult mouse ventricular myocytes. The inhibitor-1 expression levels were decreased, accompanied by enhanced PP-1 activity in the miR-765 cardiomyocytes, and these reflected depressed contractile mechanics and Ca2+ transients, compared with the miR-Ctrl group. The depressive effects were associated with decreases in the phosphorylation of phospholamban and SR Ca2+ load. These miR-765 negative inotropic effects were abrogated in inhibitor-1-deficient cardiomyocytes, suggesting its apparent specificity for inhibitor-1. miR-765 levels are increased in human failing hearts. Such increases may contribute to depressed cardiac function through reduced inhibitor-1 expression and enhanced PP-1 activity, associated with reduced SR Ca2+ load.
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