Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

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8/12/2011 0:00

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Abstract

Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells contributes critically to hypertrophic arrhythmias. The pacemaker current If, carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in determining cardiac automaticity. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. We performed a study on post-transcriptional regulation of expression of HCN2 and HCN4 genes by microRNAs. We experimentally established HCN2 as a target for repression by the muscle-specific microRNAs miR-1 and miR-133 and established HCN4 as a target for miR-1 only. We unraveled robust increases in HCN2 and HCN4 protein levels in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The up-regulation of HCN2/HCN4 was accompanied by pronounced reduction of miR-1/miR-133 levels. Forced expression of miR-1/miR-133 by transfection prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. The serum-responsive factor protein level was found significantly decreased in hypertrophic hearts, and silencing of this protein by RNA interference resulted in increased levels of miR-1/miR-133 and concomitant increases in HCN2 and HCN4 protein levels. We conclude that down-regulation of miR-1 and miR-133 expression contributes to re-expression of HCN2/HCN4 and thereby the electrical remodeling process in hypertrophic hearts. Our study also sheds new light on the cellular function and pathological role of miR-1/miR-133 in the heart. Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells contributes critically to hypertrophic arrhythmias. The pacemaker current If, carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in determining cardiac automaticity. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. We performed a study on post-transcriptional regulation of expression of HCN2 and HCN4 genes by microRNAs. We experimentally established HCN2 as a target for repression by the muscle-specific microRNAs miR-1 and miR-133 and established HCN4 as a target for miR-1 only. We unraveled robust increases in HCN2 and HCN4 protein levels in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The up-regulation of HCN2/HCN4 was accompanied by pronounced reduction of miR-1/miR-133 levels. Forced expression of miR-1/miR-133 by transfection prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. The serum-responsive factor protein level was found significantly decreased in hypertrophic hearts, and silencing of this protein by RNA interference resulted in increased levels of miR-1/miR-133 and concomitant increases in HCN2 and HCN4 protein levels. We conclude that down-regulation of miR-1 and miR-133 expression contributes to re-expression of HCN2/HCN4 and thereby the electrical remodeling process in hypertrophic hearts. Our study also sheds new light on the cellular function and pathological role of miR-1/miR-133 in the heart. Turning Down the Pacemaker Current Journal of Biological ChemistryVol. 283Issue 29PreviewDuring recovery from stress or damage, such as myocardial infarction or hypertension, the heart hypertrophies and undergoes both structural and electrical remodeling. One characteristic alteration of hypertrophic hearts is the re-expression or overexpression of the ion channel genes HCN2 and HCN4, which increases hyperpolarization-activated current (If) and contributes to the risk of arrhythmias under such pathological stress. The mechanisms behind this have been poorly understood, but in this Paper of the Week, Xiaobin Luo and colleagues convincingly show that the down-regulation of two microRNAs specifically expressed in cardiac and skeletal muscle, miR-1 and miR-133, increases HCN2 and HCN4 expression. Full-Text PDF Open AccessDown-regulation of miR-1/miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart.Journal of Biological ChemistryVol. 286Issue 32PreviewVOLUME 283 (2008) PAGES 20045–20052 Full-Text PDF Open Access The adult heart is susceptible to stress (such as hemodynamic alterations associated with myocardial infarction, hypertension, etc.) by undergoing remodeling process and hypertrophic growth to adapt to altered workloads and impaired cardiac function. The remolding process in hypertrophic hearts includes electrical remodeling that is characterized by a reprogramming of cardiac gene expression and the reactivation of “fetal” cardiac genes, with increased risk of arrhythmogenesis partially due to enhanced automaticity. In the mammalian cardiac sinus node, the pacemaker current, termed hyperpolarization-activated current (If), plays a crucial role in setting the heart rate and sensing its autonomic control. In addition to the automatic cells, If also exists in nonautomatic (non-pacemaker) regions of the heart, such as atria and ventricles, where it contributes to abnormal automatic activities (1Stilli D. Sgoifo A. Macchi E. Zaniboni M. De Iasio S. Cerbai E. Mugelli A. Lagrasta C. Olivetti G. Musso E. Am. J. Physiol. 2001; 280: H142-H150PubMed Google Scholar, 2Cerbai E. Sartiani L. DePaoli P. Pino R. Maccherini M. Bizzarri F. DiCiolla F. Davoli G. Sani G. Mugelli A. J. Mol. Cell. Cardiol. 2001; 3: 441-448Abstract Full Text PDF Scopus (113) Google Scholar, 3Fernandez-Velasco M. Goren N. Benito G. Blanco-Rivero J. Bosca L. Delgado C. J. Physiol. (Lond.). 2003; 553: 395-405Crossref Scopus (99) Google Scholar). In ventricular myocytes, If is abundantly expressed during fetal and neonatal life but progressively decreases toward adulthood in terms of the number of cells expressing If and of the density of expressed If as well (4Cerbai E. Pino R. Sartiani L. Mugelli A. Cardiovasc. Res. 1999; 42: 416-423Crossref PubMed Scopus (80) Google Scholar, 5Yasui K. Liu W. Opthof T. Kada K. Lee J.K. Kamiya K. Kodama I. Circ. Res. 2001; 88: 536-542Crossref PubMed Scopus (141) Google Scholar, 6Robinson R.B. Yu H. Chang F. Cohen I.S. Pfluegers Arch. Eur. J. Physiol. 1997; 433: 533-535Crossref PubMed Scopus (86) Google Scholar, 7Abi-Gerges N. Ji G.J. Lu Z.J. Fischmeister R. Hescheler J. Fleischmann B.K. J. Physiol. (Lond.). 2000; 523: 377-389Crossref Scopus (61) Google Scholar, 8Thuringer D. Lauribe P. Escande D. J. Mol. Cell. Cardiol. 1992; 24: 451-455Abstract Full Text PDF PubMed Scopus (35) Google Scholar). This results in a loss of the capacity of adult ventricular cells to generate spontaneous activity. Strikingly, substantial up-regulation of If expression has been observed in a variety of animal models of cardiac hypertrophy and heart failure and in human failing hearts as well (1Stilli D. Sgoifo A. Macchi E. Zaniboni M. De Iasio S. Cerbai E. Mugelli A. Lagrasta C. Olivetti G. Musso E. Am. J. Physiol. 2001; 280: H142-H150PubMed Google Scholar, 2Cerbai E. Sartiani L. DePaoli P. Pino R. Maccherini M. Bizzarri F. DiCiolla F. Davoli G. Sani G. Mugelli A. J. Mol. Cell. Cardiol. 2001; 3: 441-448Abstract Full Text PDF Scopus (113) Google Scholar, 3Fernandez-Velasco M. Goren N. Benito G. Blanco-Rivero J. Bosca L. Delgado C. J. Physiol. (Lond.). 2003; 553: 395-405Crossref Scopus (99) Google Scholar, 9Cerbai E. Pino R. Porciatti F. Sani G. Toscano M. Maccherini M. Giunti G. Mugelli A. Circulation. 1997; 95: 568-571Crossref PubMed Scopus (170) Google Scholar, 10Hoppe U.C. Jansen E. Sudkamp M. Beuckelmann D.J. Circulation. 1998; 97: 55-65Crossref PubMed Scopus (165) Google Scholar, 11Lonardo G. Stillitano F. Zicha S. Cerbai E. Mugelli A. Nattel S. Circulation. 2004; 110: III-129Google Scholar, 12Fernandez-Velasco M. Ruiz-Hurtado G. Delgado C. Pfluegers Arch. Eur. J. Physiol. 2005; 452: 146-154Crossref Scopus (11) Google Scholar, 13Cerbai E. Barbieri M. Mugelli A. J. Physiol. (Lond.). 1994; 481: 585-591Crossref Scopus (117) Google Scholar, 14Sridhar A. Dech S.J. Lacombe V.A. Elton T.S. McCune S.A. Altschuld R.A. Carnes C.A. Am. J. Physiol. 2006; 291: H2192-H2198Crossref PubMed Scopus (20) Google Scholar, 15Cerbai E. Barbieri M. Mugelli A. Circulation. 1996; 94: 1674-1681Crossref PubMed Scopus (143) Google Scholar, 16Han W. Bao W. Wang Z. Nattel S. Circ. Res. 2002; 91: 790-797Crossref PubMed Scopus (103) Google Scholar). In such circumstances, If is at least doubled in left ventricular (LV) 3The abbreviations used are: LV, left ventricular; HLV, hypertrophic left ventricle; miRNA, microRNA; siRNA, small interfering RNA; MLC, myosin light chain; AMO, antisense inhibitor oligonucleotide; UTR, untranslated region; AngII, angiotensin II; RT-PCR, reverse transcription-PCR; MHC, myosin heavy chain; SRF, serum-response factor; ANF, atrial natriuretic factor; Ctl, control; NC, negative control. cells, depending upon severity of conditions (3Fernandez-Velasco M. Goren N. Benito G. Blanco-Rivero J. Bosca L. Delgado C. J. Physiol. (Lond.). 2003; 553: 395-405Crossref Scopus (99) Google Scholar, 11Lonardo G. Stillitano F. Zicha S. Cerbai E. Mugelli A. Nattel S. Circulation. 2004; 110: III-129Google Scholar, 14Sridhar A. Dech S.J. Lacombe V.A. Elton T.S. McCune S.A. Altschuld R.A. Carnes C.A. Am. J. Physiol. 2006; 291: H2192-H2198Crossref PubMed Scopus (20) Google Scholar), and reaches values comparable with those observed in the neonatal stage. Consistently, prominent re-expression of the If-encoding genes, belonging to the hyperpolarization-activated cyclic nucleotide-gated channel (HCN) gene family in ventricular myocytes of hypertrophic heart has also been documented (17Baruscotti M. DiFrancesco D. Ann. N. Y. Acad. Sci. 2004; 1015: 111-121Crossref PubMed Scopus (66) Google Scholar, 18Qu J. Barbuti A. Protas L. Santoro B. Cohen I.S. Robinson R.B. Circ. Res. 2001; 89: E8-E14Crossref PubMed Google Scholar, 19Cohen I.S. Robinson R.B. Handb. Exp. Pharmacol. 2006; 171: 41-71Crossref PubMed Scopus (3) Google Scholar). The HCN family is composed of at least four members (HCN1–HCN4), of which HCN4 is believed to be the major molecular component for sinus If and HCN2 is believed to be the dominant isoform for ventricular If. However, mechanisms underlying the pathological re-expression of If and HCN2/HCN4 remained yet to be elucidated. Discovery of microRNAs (miRNAs) has revolutionized our understanding of the mechanisms that regulate gene expression (20Ambros V. Nature. 2004; 431: 350-355Crossref PubMed Scopus (9088) Google Scholar, 21Latronico M.V.G. Catalucci D. Condorelli G. Circ. Res. 2007; 101: 1225-1236Crossref PubMed Scopus (251) Google Scholar, 22Lewis B.P. Shih I.H. Jones-Rhoades M.W. Bartel D.P. Burge C.B. Cell. 2003; 115: Full Text Full Text PDF PubMed Scopus Google Scholar). that to in the of target of genes to repression mammalian miR-1 and miR-133 believed to specifically in adult cardiac and skeletal where miR-1 and miR-133 regulate M.V.G. Catalucci D. Condorelli G. Circ. Res. 2007; 101: 1225-1236Crossref PubMed Scopus (251) Google Scholar, Y. E. D. Nature. 2005; PubMed Scopus Google Scholar, Wang 2006; PubMed Scopus Google Scholar). that both miR-1 and miR-133 significantly in hypertrophic and failing hearts E. Liu N. J. Acad. Sci. S. A. 2006; PubMed Scopus Google Scholar, A. Catalucci D. F. D. A. P. P. Y. L. M. C. P. C. Condorelli G. 2007; PubMed Scopus Google Scholar, D. C. J. M. Circ. Res. 2007; PubMed Scopus Google Scholar), and down-regulation of miR-1 or miR-133 the of cardiac hypertrophy. of the down-regulation by expression of these the pathological This study was to light on the underlying mechanisms for re-expression of HCN2 and HCN4 in hypertrophic heart, on the role of miR-1 and miR-133 in the post-transcriptional repression of HCN2 and HCN4 of and and miR-133, and antisense inhibitor by as H. Lu Y. B. J. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar, B. H. J. Luo B. Lu Y. Wang H. Wang Z. 2007; PubMed Scopus Google Scholar, J. Luo H. C. H. Wang H. B. Wang Z. J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). of target the target for miR-1 and miR-133 or the target the of HCN2 and HCN4 or with by and The the of the gene in the expression H. Lu Y. B. J. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar, B. H. J. Luo B. Lu Y. Wang H. Wang Z. 2007; PubMed Scopus Google Scholar, J. Luo H. C. H. Wang H. B. Wang Z. J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). and by or by to the of HCN2 and HCN4 genes H. Lu Y. B. J. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar, B. H. J. Luo B. Lu Y. Wang H. Wang Z. 2007; PubMed Scopus Google Scholar, J. Luo H. C. H. Wang H. B. Wang Z. J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). used in this study was from and in hypertrophy was by an to that by (3Fernandez-Velasco M. Goren N. Benito G. Blanco-Rivero J. Bosca L. Delgado C. J. Physiol. (Lond.). 2003; 553: 395-405Crossref Scopus (99) Google Scholar, 12Fernandez-Velasco M. Ruiz-Hurtado G. Delgado C. Pfluegers Arch. Eur. J. Physiol. 2005; 452: 146-154Crossref Scopus (11) Google Scholar). adult The an of was the the left The was progressively as the and hypertrophy was established at and used as control. hearts as the of heart to of hearts. The of was in with the of the and of the and rat ventricular and as H. Lu Y. B. J. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). II-induced and of neonatal rat ventricular cells for in which for cells by angiotensin for in D. R. R. J. Mol. Cell. Cardiol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, V. S. M. J. Mol. Cell. Cardiol. 2006; Full Text Full Text PDF PubMed Scopus (86) Google Scholar). was a with a at and serum-response factor was to target the of the negative was also by as by the and by The neonatal rat ventricular cells by transfection for and and activities with a on a as H. Lu Y. B. J. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar, B. H. J. Luo B. Lu Y. Wang H. Wang Z. 2007; PubMed Scopus Google Scholar, J. Luo H. C. H. Wang H. B. Wang Z. J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). was used in with with for of miR-1 and miR-133 in our as in H. Lu Y. B. J. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar, B. H. J. Luo B. Lu Y. Wang H. Wang Z. 2007; PubMed Scopus Google Scholar, J. Luo H. C. H. Wang H. B. Wang Z. J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). for protein from neonatal rat ventricular myocytes the as in J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). protein and used as the The natriuretic heavy light and used as the expressed as of by carried was to a of HCN2 and HCN4 by miR-1 and HCN2 HCN4 is as for miR-1 and miR-133, to the by by S. Res. 2004; PubMed Google Scholar). However, by of the of target for miR-1 and for miR-133, on to the of the The of HCN4 have with four to the of miR-1 and miR-133, the the of it a of to the of miR-1 of overexpression and is a to study function J. N. R. T. M. M. Nature. 2005; PubMed Scopus Google Scholar). overexpression of in be by transfection of RNA that the the specifically and and and target by to and by as well with that HCN2 is the target of both miR-1 and miR-133 for post-transcriptional the We the of HCN2 the of a a to the of the on expression. of the with miR-1 or miR-133 cells activities to transfection of the or with the miR-1 or miR-133 to of miR-1 with or miR-133 with the silencing on miR-1 repression on with the of HCN4 the that the of HCN4 the but the of miR-133 on expression. We observed that the target of HCN2 to the of to miR-1 and to the miR-1 or the miR-133 for the the and the of miR-1 to the the for miR-1 in the of HCN4 was but the miR-1 that the HCN4 reduction of the HCN2/HCN4 repression by the by has the of the on expression of HCN2/HCN4 at the protein level in neonatal rat ventricular myocytes by of or at of HCN2 protein level of and was to increase the level by of increased HCN4 protein level by and of and a as of miR-1 or miR-133 of HCN2 but miR-1 and miR-133 decreased HCN4 level the and or to on HCN2 and HCN4 levels and that the HCN2/HCN4 to that the observed of and to or the of miR-1 and miR-133 upon transfection of the have been to target H. Lu Y. B. J. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar, B. H. J. Luo B. Lu Y. Wang H. Wang Z. 2007; PubMed Scopus Google Scholar, J. Luo H. C. H. Wang H. B. Wang Z. J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar, J. N. R. T. M. M. Nature. 2005; PubMed Scopus Google Scholar). Our this as in and significantly the levels of miR-1 and miR-133, miR-133 and miR-1 to the of the for miR-1 and miR-133 the miR-1 and miR-133 neonatal Our that the alterations of miR-1 and miR-133 levels to of miR-1 and miR-133 in of in expression at the protein level was by and HCN4 protein was found increased in the of miR-1 and miR-133 in hypertrophic overexpression of the levels of miR-1 and The miR-133 level in was found decreased by to the from hearts miR-1 level was also decreased but to a We on to the of the hypertrophic increases of HCN2/HCN4 expression by miR-1 and miR-133 levels in hypertrophic neonatal rat ventricular cardiomyocytes. increased HCN2 and HCN4 protein levels increases with of cells with miR-1 and miR-133 In the of the prevented by of and to with the up-regulation of HCN2/HCN4 also decreased miR-1 and miR-133 levels the neonatal the transfection of miR-1 and miR-133, that miR-1/miR-133 increased the cellular levels of miR-1/miR-133 of in of HCN2 and HCN4 in has been that expression of is upon of to regions Y. E. D. Nature. 2005; PubMed Scopus Google Scholar, Wang 2006; PubMed Scopus Google Scholar). We the role of in to HCN2/HCN4 expression. expression at both and protein levels was found significantly decreased in hypertrophic left to hearts of adult that down-regulation of miR-1/miR-133 the of silencing of by an on miR-1/miR-133 levels in neonatal rat ventricular in significantly miR-1 and miR-133 levels. increased HCN2 and HCN4 protein levels The of to expression was at both and protein levels in rat cells The negative to and expressions an for the performed the of the on the levels of two genes and H. J. Luo C. H. Wang H. B. Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). in the to the levels of these In as a also the of the on the level of it has been that the of gene an and that G. J. P. K. T. J. K. J. Am. J. Physiol. 2001; 280: PubMed Google Scholar). The in that the the level of the to results with the down-regulation of in hypertrophic hearts in light of the that is also in hypertrophic heart as in this study to that the myocytes with angiotensin hypertrophic the of and expression of for cardiac hypertrophy and 2006; PubMed Scopus Google Scholar). in and the was significantly and and in expression. the of repression of and by miR-1/miR-133 underlying the hypertrophic of HCN2/HCN4 the of of miR-1/miR-133 to the protein levels of and in rat myocytes In and the of miR-1 or miR-133 in the of and One of the characteristic alterations of hypertrophic hearts is the re-expression or overexpression of pacemaker channel genes, and thereby If current, which contributes to the enhanced and the risk of arrhythmias under such pathological conditions (1Stilli D. Sgoifo A. Macchi E. Zaniboni M. De Iasio S. Cerbai E. Mugelli A. Lagrasta C. Olivetti G. Musso E. Am. J. Physiol. 2001; 280: H142-H150PubMed Google Scholar, 2Cerbai E. Sartiani L. DePaoli P. Pino R. Maccherini M. Bizzarri F. DiCiolla F. Davoli G. Sani G. Mugelli A. J. Mol. Cell. Cardiol. 2001; 3: 441-448Abstract Full Text PDF Scopus (113) Google Scholar, 3Fernandez-Velasco M. Goren N. Benito G. Blanco-Rivero J. Bosca L. Delgado C. J. Physiol. (Lond.). 2003; 553: 395-405Crossref Scopus (99) Google Scholar, 9Cerbai E. Pino R. Porciatti F. Sani G. Toscano M. Maccherini M. Giunti G. Mugelli A. Circulation. 1997; 95: 568-571Crossref PubMed Scopus (170) Google Scholar, 10Hoppe U.C. Jansen E. Sudkamp M. Beuckelmann D.J. Circulation. 1998; 97: 55-65Crossref PubMed Scopus (165) Google Scholar, 11Lonardo G. Stillitano F. Zicha S. Cerbai E. Mugelli A. Nattel S. Circulation. 2004; 110: III-129Google Scholar, 12Fernandez-Velasco M. Ruiz-Hurtado G. Delgado C. Pfluegers Arch. Eur. J. Physiol. 2005; 452: 146-154Crossref Scopus (11) Google Scholar, 13Cerbai E. Barbieri M. Mugelli A. J. Physiol. (Lond.). 1994; 481: 585-591Crossref Scopus (117) Google Scholar, 14Sridhar A. Dech S.J. Lacombe V.A. Elton T.S. McCune S.A. Altschuld R.A. Carnes C.A. Am. J. Physiol. 2006; 291: H2192-H2198Crossref PubMed Scopus (20) Google Scholar, 15Cerbai E. Barbieri M. Mugelli A. Circulation. 1996; 94: 1674-1681Crossref PubMed Scopus (143) Google Scholar, 16Han W. Bao W. Wang Z. Nattel S. Circ. Res. 2002; 91: 790-797Crossref PubMed Scopus (103) Google Scholar). However, the mechanisms remained poorly In this overexpression of HCN2 and HCN4 in hypertrophy by an and in neonatal hypertrophy by angiotensin We experimentally established HCN2 and HCN4 genes as for post-transcriptional repression by the muscle-specific miR-1 and The up-regulation of HCN2 and HCN4 was accompanied by substantial decreases in miR-1/miR-133 levels. of miR-1/miR-133 down-regulation prevented overexpression of HCN2/HCN4 in hypertrophy We conclude that down-regulation of miR-1 and miR-133 expression contributes to the re-expression of and thereby the electrical remodeling process in hypertrophic hearts. Our study also sheds new light on the cellular function of miR-1 and miR-133 in the heart and on the regulation of ion channel genes by these miR-1 and miR-133 expressed in a during and during the of Y. E. D. Nature. 2005; PubMed Scopus Google Scholar, Wang 2006; PubMed Scopus Google Scholar). expression of miR-1 and miR-133 has been found in neonatal hearts, and levels in adult cardiac Wang 2006; PubMed Scopus Google Scholar). This at least partially for the decreased If density in adult ventricular cells (1Stilli D. Sgoifo A. Macchi E. Zaniboni M. De Iasio S. Cerbai E. Mugelli A. Lagrasta C. Olivetti G. Musso E. Am. J. Physiol. 2001; 280: H142-H150PubMed Google Scholar, 2Cerbai E. Sartiani L. DePaoli P. Pino R. Maccherini M. Bizzarri F. DiCiolla F. Davoli G. Sani G. Mugelli A. J. Mol. Cell. Cardiol. 2001; 3: 441-448Abstract Full Text PDF Scopus (113) Google Scholar, 3Fernandez-Velasco M. Goren N. Benito G. Blanco-Rivero J. Bosca L. Delgado C. J. Physiol. (Lond.). 2003; 553: 395-405Crossref Scopus (99) Google for enhanced expression HCN2/HCN4 expression. this factor as in hypertrophic myocytes where levels HCN2/HCN4 The of miR-1/miR-133 on HCN2/HCN4 expression to post-transcriptional of of HCN2/HCN4 protein in miR-1 and miR-133 hypertrophic hearts found in this study with the E. Liu N. J. Acad. Sci. S. A. 2006; PubMed Scopus Google Scholar, A. Catalucci D. F. D. A. P. P. Y. L. M. C. P. C. Condorelli G. 2007; PubMed Scopus Google Scholar, D. C. J. M. Circ. Res. 2007; PubMed Scopus Google Scholar). The study a the role of miR-1/miR-133 by in the heart. Our results that as with the of a is for a target to with the to repression B.P. Shih I.H. Jones-Rhoades M.W. Bartel D.P. Burge C.B. Cell. 2003; 115: Full Text Full Text PDF PubMed Scopus Google Scholar). This of has been as the of HCN4 such it has a of well to the of and this of is for miR-1 to to HCN4 and to the The that such a of repression as with the that the of and contributing to to on the HCN2 protein of and is and of the two to HCN2 This is to the that HCN2 is by miR-1 and miR-133, and of of the is to reverse the by the both the repression be The study at understanding the underlying mechanisms for the re-expression of HCN2 and HCN4 in hypertrophic and our the altered expression of miR-1/miR-133 as of the important The of of miR-1 and miR-133 on expression of ANF, and that the down-regulation of miR-1/miR-133 and up-regulation of HCN2/HCN4 and that hypertrophic be in the be that regulation of HCN2/HCN4 expression be a and our study the of miR-1/miR-133 to this process but at We have also the of HCN2 and HCN4 expression at the level in hypertrophic hearts. Our that the levels of HCN2 and HCN4 also but to to the increases at the protein with and increases in HCN2 and HCN4 with and increases in protein levels. This be by a of the post-transcriptional repression of HCN2 and HCN4 expression due to down-regulation of miR-1 and However, our study the mechanisms for the up-regulation of HCN2 and HCN4 at the Our study also down-regulation of expression as a for the up-regulation of HCN2 and HCN4 expression down-regulation of miR-1/miR-133 in hypertrophic of miR-1/miR-133 has been to critically upon to regions Y. E. D. Nature. 2005; PubMed Scopus Google Scholar, Wang 2006; PubMed Scopus Google Scholar). In with the of expression in hypertrophic heart, in failing hearts of both and a substantial in expression of accompanied by robust expression of a dominant negative isoform has been documented R. 2003; PubMed Scopus Google Scholar, M. E. V. Am. J. Physiol. 2002; PubMed Scopus Google Scholar). Our that expression of miR-1 and miR-133 be a for overexpression of and the associated arrhythmias in hypertrophic hearts. is the that have J. B. H. Lu Y. Luo Wang Z. J. Cell. Physiol. 2007; PubMed Scopus Google Scholar). This specifically to the target genes such as HCN2 and We have the of the for HCN2 and HCN4 in expression and function in a We for with

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The record

Venue

Journal of Biological Chemistry

Topic

MicroRNA in disease regulation

Field

Biochemistry, Genetics and Molecular Biology

Canadian institutions

Université de MontréalMontreal Heart Institute

Funders

—

Keywords

microRNAGeneGene expressionChannel (broadcasting)BiologyInternal medicineCardiologyCell biologyGeneticsMedicineComputer scienceTelecommunications

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