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MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex

In heart failure (HF), arrhythmogenic spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and afterdepolarizations in cardiac myocytes have been linked to abnormally high activity of ryanodine receptors (RyR2s) associated with enhanced phosphorylation of the channel. However, the specific molecul...

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Published in:PloS one 2011-12, Vol.6 (12), p.e28324-e28324
Main Authors: Belevych, Andriy E, Sansom, Sarah E, Terentyeva, Radmila, Ho, Hsiang-Ting, Nishijima, Yoshinori, Martin, Mickey M, Jindal, Hitesh K, Rochira, Jennifer A, Kunitomo, Yukiko, Abdellatif, Maha, Carnes, Cynthia A, Elton, Terry S, Györke, Sandor, Terentyev, Dmitry
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cited_by cdi_FETCH-LOGICAL-c757t-31606231a8b3e5292c0c489477fa9fb06b35820a995891be8bc953a9b92d0e4f3
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creator Belevych, Andriy E
Sansom, Sarah E
Terentyeva, Radmila
Ho, Hsiang-Ting
Nishijima, Yoshinori
Martin, Mickey M
Jindal, Hitesh K
Rochira, Jennifer A
Kunitomo, Yukiko
Abdellatif, Maha
Carnes, Cynthia A
Elton, Terry S
Györke, Sandor
Terentyev, Dmitry
description In heart failure (HF), arrhythmogenic spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and afterdepolarizations in cardiac myocytes have been linked to abnormally high activity of ryanodine receptors (RyR2s) associated with enhanced phosphorylation of the channel. However, the specific molecular mechanisms underlying RyR2 hyperphosphorylation in HF remain poorly understood. The objective of the current study was to test the hypothesis that the enhanced expression of muscle-specific microRNAs (miRNAs) underlies the HF-related alterations in RyR2 phosphorylation in ventricular myocytes by targeting phosphatase activity localized to the RyR2. We studied hearts isolated from canines with chronic HF exhibiting increased left ventricular (LV) dimensions and decreased LV contractility. qRT-PCR revealed that the levels of miR-1 and miR-133, the most abundant muscle-specific miRNAs, were significantly increased in HF myocytes compared with controls (2- and 1.6-fold, respectively). Western blot analyses demonstrated that expression levels of the protein phosphatase 2A (PP2A) catalytic and regulatory subunits, which are putative targets of miR-133 and miR-1, were decreased in HF cells. PP2A catalytic subunit mRNAs were validated as targets of miR-133 by using luciferase reporter assays. Pharmacological inhibition of phosphatase activity increased the frequency of diastolic Ca(2+) waves and afterdepolarizations in control myocytes. The decreased PP2A activity observed in HF was accompanied by enhanced Ca(2+)/calmodulin-dependent protein kinase (CaMKII)-mediated phosphorylation of RyR2 at sites Ser-2814 and Ser-2030 and increased frequency of diastolic Ca(2+) waves and afterdepolarizations in HF myocytes compared with controls. In HF myocytes, CaMKII inhibitory peptide normalized the frequency of pro-arrhythmic spontaneous diastolic Ca(2+) waves. These findings suggest that altered levels of major muscle-specific miRNAs contribute to abnormal RyR2 function in HF by depressing phosphatase activity localized to the channel, which in turn, leads to the excessive phosphorylation of RyR2s, abnormal Ca(2+) cycling, and increased propensity to arrhythmogenesis.
doi_str_mv 10.1371/journal.pone.0028324
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However, the specific molecular mechanisms underlying RyR2 hyperphosphorylation in HF remain poorly understood. The objective of the current study was to test the hypothesis that the enhanced expression of muscle-specific microRNAs (miRNAs) underlies the HF-related alterations in RyR2 phosphorylation in ventricular myocytes by targeting phosphatase activity localized to the RyR2. We studied hearts isolated from canines with chronic HF exhibiting increased left ventricular (LV) dimensions and decreased LV contractility. qRT-PCR revealed that the levels of miR-1 and miR-133, the most abundant muscle-specific miRNAs, were significantly increased in HF myocytes compared with controls (2- and 1.6-fold, respectively). Western blot analyses demonstrated that expression levels of the protein phosphatase 2A (PP2A) catalytic and regulatory subunits, which are putative targets of miR-133 and miR-1, were decreased in HF cells. 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PP2A catalytic subunit mRNAs were validated as targets of miR-133 by using luciferase reporter assays. Pharmacological inhibition of phosphatase activity increased the frequency of diastolic Ca(2+) waves and afterdepolarizations in control myocytes. The decreased PP2A activity observed in HF was accompanied by enhanced Ca(2+)/calmodulin-dependent protein kinase (CaMKII)-mediated phosphorylation of RyR2 at sites Ser-2814 and Ser-2030 and increased frequency of diastolic Ca(2+) waves and afterdepolarizations in HF myocytes compared with controls. In HF myocytes, CaMKII inhibitory peptide normalized the frequency of pro-arrhythmic spontaneous diastolic Ca(2+) waves. 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metabolism</topic><topic>miRNA</topic><topic>Models, Biological</topic><topic>Molecular modelling</topic><topic>Muscle Cells - metabolism</topic><topic>Muscle contraction</topic><topic>Muscles</topic><topic>Myocytes</topic><topic>Pharmacology</topic><topic>Pharmacy</topic><topic>Phosphatase</topic><topic>Phosphatases</topic><topic>Phosphoprotein phosphatase</topic><topic>Phosphoric Monoester Hydrolases - metabolism</topic><topic>Phosphorylation</topic><topic>Physiology</topic><topic>Protein folding</topic><topic>Protein phosphatase</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Receptors, Adrenergic, beta - metabolism</topic><topic>Regulatory subunits</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><topic>Ryanodine Receptor Calcium Release Channel - metabolism</topic><topic>Ryanodine receptors</topic><topic>Sarcoplasmic reticulum</topic><topic>Sarcoplasmic Reticulum - metabolism</topic><topic>Ventricle</topic><topic>Veterinary Science</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Belevych, Andriy E</creatorcontrib><creatorcontrib>Sansom, Sarah E</creatorcontrib><creatorcontrib>Terentyeva, Radmila</creatorcontrib><creatorcontrib>Ho, Hsiang-Ting</creatorcontrib><creatorcontrib>Nishijima, Yoshinori</creatorcontrib><creatorcontrib>Martin, Mickey M</creatorcontrib><creatorcontrib>Jindal, Hitesh K</creatorcontrib><creatorcontrib>Rochira, Jennifer A</creatorcontrib><creatorcontrib>Kunitomo, Yukiko</creatorcontrib><creatorcontrib>Abdellatif, Maha</creatorcontrib><creatorcontrib>Carnes, Cynthia A</creatorcontrib><creatorcontrib>Elton, Terry S</creatorcontrib><creatorcontrib>Györke, Sandor</creatorcontrib><creatorcontrib>Terentyev, Dmitry</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints Resource Center</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database (ProQuest)</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>ProQuest advanced technologies &amp; aerospace journals</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials science collection</collection><collection>ProQuest Publicly Available Content database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Belevych, Andriy E</au><au>Sansom, Sarah E</au><au>Terentyeva, Radmila</au><au>Ho, Hsiang-Ting</au><au>Nishijima, Yoshinori</au><au>Martin, Mickey M</au><au>Jindal, Hitesh K</au><au>Rochira, Jennifer A</au><au>Kunitomo, Yukiko</au><au>Abdellatif, Maha</au><au>Carnes, Cynthia A</au><au>Elton, Terry S</au><au>Györke, Sandor</au><au>Terentyev, Dmitry</au><au>Rota, Marcello</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-12-06</date><risdate>2011</risdate><volume>6</volume><issue>12</issue><spage>e28324</spage><epage>e28324</epage><pages>e28324-e28324</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>In heart failure (HF), arrhythmogenic spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and afterdepolarizations in cardiac myocytes have been linked to abnormally high activity of ryanodine receptors (RyR2s) associated with enhanced phosphorylation of the channel. However, the specific molecular mechanisms underlying RyR2 hyperphosphorylation in HF remain poorly understood. The objective of the current study was to test the hypothesis that the enhanced expression of muscle-specific microRNAs (miRNAs) underlies the HF-related alterations in RyR2 phosphorylation in ventricular myocytes by targeting phosphatase activity localized to the RyR2. We studied hearts isolated from canines with chronic HF exhibiting increased left ventricular (LV) dimensions and decreased LV contractility. qRT-PCR revealed that the levels of miR-1 and miR-133, the most abundant muscle-specific miRNAs, were significantly increased in HF myocytes compared with controls (2- and 1.6-fold, respectively). Western blot analyses demonstrated that expression levels of the protein phosphatase 2A (PP2A) catalytic and regulatory subunits, which are putative targets of miR-133 and miR-1, were decreased in HF cells. PP2A catalytic subunit mRNAs were validated as targets of miR-133 by using luciferase reporter assays. Pharmacological inhibition of phosphatase activity increased the frequency of diastolic Ca(2+) waves and afterdepolarizations in control myocytes. The decreased PP2A activity observed in HF was accompanied by enhanced Ca(2+)/calmodulin-dependent protein kinase (CaMKII)-mediated phosphorylation of RyR2 at sites Ser-2814 and Ser-2030 and increased frequency of diastolic Ca(2+) waves and afterdepolarizations in HF myocytes compared with controls. In HF myocytes, CaMKII inhibitory peptide normalized the frequency of pro-arrhythmic spontaneous diastolic Ca(2+) waves. These findings suggest that altered levels of major muscle-specific miRNAs contribute to abnormal RyR2 function in HF by depressing phosphatase activity localized to the channel, which in turn, leads to the excessive phosphorylation of RyR2s, abnormal Ca(2+) cycling, and increased propensity to arrhythmogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22163007</pmid><doi>10.1371/journal.pone.0028324</doi><tpages>e28324</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2011-12, Vol.6 (12), p.e28324-e28324
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1311466253
source PubMed Central(OpenAccess); ProQuest Publicly Available Content database
subjects Animals
Arrhythmia
Arrhythmias, Cardiac - genetics
Arrhythmias, Cardiac - metabolism
Biology
Ca2+/calmodulin-dependent protein kinase II
Calcium (reticular)
Calcium - metabolism
Calcium binding proteins
Calcium signalling
Calcium-binding protein
Calmodulin
Cardiology
Cardiomyocytes
Cardiomyopathy
Catalysis
Catalytic Domain
Dogs
Electrophysiology - methods
Fibroblasts
Gene expression
Genes, Reporter
Heart
Heart attacks
Heart diseases
Heart failure
Heart Failure - complications
Heart Failure - metabolism
Heart Ventricles - pathology
Hospitals
Humans
Isoproterenol - pharmacology
Kinases
Luciferase
Medical schools
Medicine
MicroRNA
MicroRNAs
MicroRNAs - metabolism
miRNA
Models, Biological
Molecular modelling
Muscle Cells - metabolism
Muscle contraction
Muscles
Myocytes
Pharmacology
Pharmacy
Phosphatase
Phosphatases
Phosphoprotein phosphatase
Phosphoric Monoester Hydrolases - metabolism
Phosphorylation
Physiology
Protein folding
Protein phosphatase
Proteins
Receptors
Receptors, Adrenergic, beta - metabolism
Regulatory subunits
Ribonucleic acid
RNA
RNA, Messenger - metabolism
Rodents
Ryanodine Receptor Calcium Release Channel - metabolism
Ryanodine receptors
Sarcoplasmic reticulum
Sarcoplasmic Reticulum - metabolism
Ventricle
Veterinary Science
title MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex
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