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dc.contributor.authorAli, Rahmat
dc.contributor.authorHuang, Yan
dc.contributor.authorMaher, Stephen E
dc.contributor.authorKim, Richard W
dc.contributor.authorGiordano, Frank J
dc.contributor.authorTellides, George
dc.contributor.authorGeirsson, Arnar
dc.date.accessioned2013-07-02T09:28:38Z
dc.date.available2013-07-02T09:28:38Z
dc.date.issued2012-05
dc.date.submitted2012-07-02
dc.identifier.citationJ. Mol. Cell. Cardiol. 2012, 52 (5):1027-37en_GB
dc.identifier.issn1095-8584
dc.identifier.pmid22326846
dc.identifier.doi10.1016/j.yjmcc.2012.01.020
dc.identifier.urihttp://hdl.handle.net/2336/295062
dc.description.abstractMicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1. The importance of miR-1 was established by miR-1 antagomir treatment of wild-type mice, which replicated the cardiac-specific Dicer knockdown phenotype. Down-regulation of miR-1 was associated with up-regulation of its predicted target Sorcin, an established modulator of calcium signaling and excitation-contraction coupling, subsequently verified as a miR-1 target with luciferase constructs. siRNA-mediated knockdown of Sorcin effectively rescued the cardiac phenotypes after Dicer or miR-1 knockdown affirming Sorcin as a critical mediator of the acute cardiomyopathy observed. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels and dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in end-stage cardiomyopathy. These findings demonstrate the importance of miR-1 in cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.
dc.description.sponsorshipThoracic Surgery Foundation for Research and Education Charles W. Oshe Funds Research Granten_GB
dc.language.isoenen
dc.relation.urlhttp://dx.doi.org/10.1016/j.yjmcc.2012.01.020en_GB
dc.rightsArchived with thanks to Journal of molecular and cellular cardiologyen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshBase Sequenceen_GB
dc.subject.meshCalcium Signalingen_GB
dc.subject.meshCalcium-Binding Proteinsen_GB
dc.subject.meshCardiac Volumeen_GB
dc.subject.meshCardiomyopathiesen_GB
dc.subject.meshCell Lineen_GB
dc.subject.meshDEAD-box RNA Helicasesen_GB
dc.subject.meshHearten_GB
dc.subject.meshHumansen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, 129 Strainen_GB
dc.subject.meshMice, Inbred C57BLen_GB
dc.subject.meshMice, Knockouten_GB
dc.subject.meshMicroRNAsen_GB
dc.subject.meshMyocardial Contractionen_GB
dc.subject.meshMyocardiumen_GB
dc.subject.meshRNA Interferenceen_GB
dc.subject.meshRNA, Small Interferingen_GB
dc.subject.meshRibonuclease IIIen_GB
dc.subject.meshUp-Regulationen_GB
dc.titlemiR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling.en
dc.typeArticleen
dc.contributor.departmentSection of Cardiac Surgery, Department of Surgery, Yale University, New Haven, CT 06510, USA.en_GB
dc.identifier.journalJournal of molecular and cellular cardiologyen_GB
dc.rights.accessNational Consortium - Landsaðganguren
html.description.abstractMicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1. The importance of miR-1 was established by miR-1 antagomir treatment of wild-type mice, which replicated the cardiac-specific Dicer knockdown phenotype. Down-regulation of miR-1 was associated with up-regulation of its predicted target Sorcin, an established modulator of calcium signaling and excitation-contraction coupling, subsequently verified as a miR-1 target with luciferase constructs. siRNA-mediated knockdown of Sorcin effectively rescued the cardiac phenotypes after Dicer or miR-1 knockdown affirming Sorcin as a critical mediator of the acute cardiomyopathy observed. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels and dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in end-stage cardiomyopathy. These findings demonstrate the importance of miR-1 in cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.


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