Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy

Li, Qing; Song, Xiaowei; Zou, Jun; Wang, Guokun; Kremneva, Elena; Li, Xiangqi; Zhu, Ning; Sun, Tao; Lappalainen, Pekka; Wang, Yuan; Qin, Yue; Jing, Qing

doi:10.1242/jcs.067165

Cited by 129 publications

(79 citation statements)

References 44 publications

(68 reference statements)

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“…We chose these two miRNAs because they have important roles in cardiomyocyte biology. miR-1 is highly conserved throughout species, is the most abundant miRNA in human adult hearts (ϳ24%), and is also lethal in homozygous knockdown mice (13,15,49). miR-21 is one of the most consistently up-regulated miRNAs in cardiac hypertrophy, and inhibition of miR-21 enhances hypertrophic growth (13,47,48).…”

Section: Discussionmentioning

confidence: 99%

Reversal of Phospholamban Inhibition of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) Using Short, Protein-interacting RNAs and Oligonucleotide Analogs

Soller¹,

Yang²,

Veglia

et al. 2016

Journal of Biological Chemistry

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The sarco(endo)plasmic reticulum Ca 2؉ -ATPase (SERCA) and phospholamban (PLN) complex regulates heart relaxation through its removal of cytosolic Ca 2؉ during diastole. Dysfunction of this complex has been related to many heart disorders and is therefore a key pharmacological target. There are currently no therapeutics that directly target either SERCA or PLN. It has been previously reported that single-stranded DNA binds PLN with strong affinity and relieves inhibition of SERCA in a length-dependent manner. In the current article, we demonstrate that RNAs and single-stranded oligonucleotide analogs, or xeno nucleic acids (XNAs), also bind PLN strongly (K d <10 nM) and relieve inhibition of SERCA. Affinity for PLN is sequence-independent. Relief of PLN inhibition is length-dependent, allowing SERCA activity to be restored incrementally. The improved in vivo stability of XNAs offers more realistic pharmacological potential than DNA or RNA. We also found that microRNAs (miRNAs) 1 and 21 bind PLN strongly and relieve PLN inhibition of SERCA to a greater extent than a similar length random sequence RNA mixture. This may suggest that miR-1 and miR-21 have evolved to contain distinct sequence elements that are more effective at relieving PLN inhibition than random sequences.Calcium cycling in cardiomyocytes is a tightly regulated process that ensures proper muscle contractility (1, 2). Many of the proteins involved in this cycle have been implicated in cardiac failure, the leading cause of death world-wide (3, 4). Given the complexity of heart failure phenotypes, strategies for reversing declining cardiac performance are diverse and necessary. Gene therapy efforts for inherited forms of heart disease have been growing, but with the recent failure of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trials, drug development targeting specific proteins remains an essential, complimentary effort (5-7). A therapeutic that is tunable to specific phenotypes would be ideal for reversing aberrant calcium cycling.The sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) 3 is an essential Ca 2ϩ -handling protein that removes Ca 2ϩ ions from the cytosol, causing the heart muscle to relax. SERCA is a P-type ATPase, which in human cardiomyocytes is responsible for the removal of ϳ70% of Ca 2ϩ from the cytosol (8). This process, coupled with other Ca 2ϩ transport mechanisms, lowers the cytosolic Ca 2ϩ concentration enough to allow for muscle relaxation (diastole) (1). Phospholamban (PLN) is a 52-amino acid, single-pass transmembrane protein that inhibits SERCA when not phosphorylated by lowering its apparent calcium affinity and hampering Ca 2ϩ transport into the sarcoplasmic reticulum (9, 10). Upon ␤-adrenergic stimulation, protein kinase A (PKA) will phosphorylate PLN at Ser-16, restoring the apparent calcium affinity and Ca 2ϩ transport of SERCA (11). We previously reported that random sequence, singlestranded DNA and RNA bind to PLN with high affinity (K d Ͻ 10 nM), and more import...

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Section: Discussionmentioning

confidence: 99%

Reversal of Phospholamban Inhibition of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) Using Short, Protein-interacting RNAs and Oligonucleotide Analogs

Soller¹,

Yang²,

Veglia

et al. 2016

Journal of Biological Chemistry

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“…However, additional studies are required in order to investigate the role of miR-26a in vivo. Abundant miR-26a expression is present in the heart tissues of rats and humans (14,15), with decreased levels in ischemic preconditioning. Studies into the role of miR-26a have also been performed in a number of cancer cell types.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-26a induces osteosarcoma cell growth and metastasis via the Wnt/β-catenin pathway

Yuan

et al. 2015

Oncology Letters

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Abstract. MicroRNAs (miRNAs/miRs) are a type of highly conserved, small non-coding RNA that are vital to the post-transcriptional regulation of gene expression via base pairing with target mRNA 3'-untranslated regions (3'-UTRs). Several studies have indicated that the abnormal expression of miRNAs occurs frequently in human osteosarcoma (OS). In the present study, the role of miR-26a in the progression and metastasis of OS was investigated using reverse transcription-quantitative polymerase chain reaction, a luciferase activity assay, cell viability assay, in vitro migration and invasion assays, transfection and western blot analysis. miR-26a was upregulated in OS tissues and cell lines, and the expression of miR-26a was indicated to affect the proliferation, migration and invasion of OS Saos-2 cells. At the molecular level, the results showed that glycogen synthase kinase-3β (GSK-3β) was identified as a target of miR-26a, and the ectopic expression of miR-26a inhibited GSK-3β by directly binding to the 3'-UTR. Therefore, the expression of miR-26a was negatively correlated with GSK-3β in the OS tissues. These data suggest that miR-26a is significant in the proliferation of human OS cells due to the direct regulation of Wnt/β-catenin signaling. IntroductionOsteosarcoma (OS) is the most common primary malignant bone tumor, occurring frequently in adolescents and possessing a high malignant severity (1-4). OS is commonly identified on the distal femur and proximal tibia, possessing high rates of recurrence and metastasis, and a poor prognosis. Previously, surgical resection therapy resulted in a poor prognosis for OS patients (2). At present, the molecular pathogenesis and etiology of OS remain unclear. Therefore, the identification of the effector molecules or signaling pathways responsible for regulating tumor growth and metastasis is critical for improving OS treatment.MicroRNAs (miRNAs/miRs) are a type of highly conserved, small non-coding RNA that are vital to the post-transcriptional regulation of gene expression via base pairing with target mRNA 3'-untranslated regions (3'-UTRs) (5,6). Previous studies have indicated that the abnormal expression of miRNAs is closely associated with cell proliferation, apoptosis, metastasis and invasion in human cancers, including OS (7,8). miRNAs function as either tumor suppressors or oncogenes, depending on the role of the target genes. Previous studies have indicated that the inhibition of miR-26a may induce increased apoptosis in primary cultured chronic lymphocytic leukemia cells through suppression of phosphatase and tensin homolog (9). In addition, miR-26a inhibits hepatitis B virus transcription and replication by targeting the host factor cysteine and histidine-rich domain-containing, zinc-binding protein 1 (10).In the present study, the miRNA expression profiles of human OS samples and cell lines were compared with those of adjacent normal skeletal muscle and normal cell lines. miR-26a was indicated to be upregulated in human OS and cell lines, and the expression o...

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“…MiR-1 was shown to be significantly down-regulated after pressure-overload-induced CH in rat and mouse models (129,130). Interestingly, this down-regulation of miR-1 was observed as one of the earliest events in the heart after aortic constriction-induced hypertrophy-even before the increase of cardiomyocyte cell mass emerges (131).…”

Section: Regulation Of Hypertrophymentioning

confidence: 98%

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

et al. 2017

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Congenital heart disease (CHD) is the leading cause of infant death, affecting approximately 4-14 live births per 1,000. Although surgical techniques and interventions have improved significantly, a large number of infants still face poor clinical outcomes. MicroRNAs (miRs) are known to coordinately regulate cardiac development and stimulate pathological processes in the heart, including fibrosis or hypertrophy and impair angiogenesis. Dysregulation of these regulators could therefore contribute (I) to the initial development of CHD and (II) at least partially to the observed clinical outcomes of many CHD patients by stimulating the aforementioned pathways. Thus, miRs may exhibit great potential as therapeutic targets in regenerative medicine. In this review we provide an overview of miR function and elucidate their role in selected CHDs, including hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TOF), ventricular septal defects (VSDs) and Holt-Oram syndrome (HOS). We then bridge this knowledge to the potential usefulness of miRs and/or their targets in therapeutic strategies for regenerative purposes in CHDs.

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Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy

Cited by 129 publications

References 44 publications

Reversal of Phospholamban Inhibition of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) Using Short, Protein-interacting RNAs and Oligonucleotide Analogs

Reversal of Phospholamban Inhibition of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) Using Short, Protein-interacting RNAs and Oligonucleotide Analogs

MicroRNA-26a induces osteosarcoma cell growth and metastasis via the Wnt/β-catenin pathway

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

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