MicroRNA miR-133 Represses HERG K+ Channel Expression Contributing to QT Prolongation in Diabetic Hearts

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8/12/2011 0:00

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Résumé

We have previously found that the ether-a-go-go related gene (ERG), a long QT syndrome gene encoding a key K+ channel (IKr) in cardiac cells, is severely depressed in its expression at the protein level but not at the mRNA level in diabetic subjects. The mechanisms underlying the disparate alterations of ERG protein and mRNA, however, remained unknown. We report here a remarkable overexpression of miR-133 in hearts from a rabbit model of diabetes, and in parallel the expression of serum response factor (SRF), which is known to be a transactivator of miR-133, was also robustly increased. Delivery of exogenous miR-133 into the rabbit myocytes and cell lines produced post-transcriptional repression of ERG, down-regulating ERG protein level without altering its transcript level and caused substantial depression of IKr, an effect abrogated by the miR-133 antisense inhibitor. Functional inhibition or gene silencing of SRF down-regulated miR-133 expression and increased IKr density. Repression of ERG by miR-133 likely underlies the differential changes of ERG protein and transcript thereby depression of IKr, and contributes to repolarization slowing thereby QT prolongation and the associated arrhythmias, in diabetic hearts. Our study provided the first evidence for the pathological role of miR-133 in adult hearts and thus expanded our understanding of the cellular function and pathophysiological roles of miRNAs. We have previously found that the ether-a-go-go related gene (ERG), a long QT syndrome gene encoding a key K+ channel (IKr) in cardiac cells, is severely depressed in its expression at the protein level but not at the mRNA level in diabetic subjects. The mechanisms underlying the disparate alterations of ERG protein and mRNA, however, remained unknown. We report here a remarkable overexpression of miR-133 in hearts from a rabbit model of diabetes, and in parallel the expression of serum response factor (SRF), which is known to be a transactivator of miR-133, was also robustly increased. Delivery of exogenous miR-133 into the rabbit myocytes and cell lines produced post-transcriptional repression of ERG, down-regulating ERG protein level without altering its transcript level and caused substantial depression of IKr, an effect abrogated by the miR-133 antisense inhibitor. Functional inhibition or gene silencing of SRF down-regulated miR-133 expression and increased IKr density. Repression of ERG by miR-133 likely underlies the differential changes of ERG protein and transcript thereby depression of IKr, and contributes to repolarization slowing thereby QT prolongation and the associated arrhythmias, in diabetic hearts. Our study provided the first evidence for the pathological role of miR-133 in adult hearts and thus expanded our understanding of the cellular function and pathophysiological roles of miRNAs. MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts.Journal of Biological ChemistryVol. 286Issue 32PreviewVOLUME 282 (2007) PAGES 12363–12367 Full-Text PDF Open Access Abnormal QT interval prolongation is a prominent electrical disorder and has been proposed a predictor of mortality in patients with diabetes mellitus (DM), 3The abbreviations used are: DM, diabetes mellitus; AMO-1 and AMO-133, anti-miRNA oligonucleotides specific for the muscle-specific miRNAs miR-1 and miR-133, respectively; ERG, ether-a-go-go related gene; rbERG, rabbit ERG; HERG, human ERG; IKr, rapid delayed rectifier K+ current; miRNA, microRNA; SRF, serum response factor; SRF-siRNA, small interference RNA against SRF; RT, reverse transcription; qRT, quantitative RT. presumably because it is associated with an increased risk of sudden cardiac death consequent to lethal ventricular arrhythmias (1Christensen P.K. Gall M.A. Major-Pedersen A. Sato A. Rossing P. Breum L. Pietersen A. Kastrup J. Parving H.H. Scand. J. Clin. Lab. Invest. 2000; 60: 323-332Crossref PubMed Scopus (82) Google Scholar, 2Okin P.M. Devereux R.B. Lee E.T. Galloway J.M. Howard B.V. Diabetes. 2004; 53: 434-440Crossref PubMed Scopus (99) Google Scholar, 3Rossing P. Breum L. Major-Peteresen A. Sato A. Winding H. Pietersen A. Kastrup J. Parving H.H. Diabet. Med. 2001; 18: 199-205Crossref PubMed Scopus (150) Google Scholar, 4Veglio M. Chinaglia A. Cavallo-Perin P. J. Endocrinol. Invest. 2004; 27: 175-181Crossref PubMed Scopus (106) Google Scholar, 5Rana B.S. Lim P.O. Naas A.A.O. Ogston S.A. Newton R.W. Jung R.T. Morris A.D. Struthers A.D. Heart. 2005; 91: 44-50Crossref PubMed Scopus (64) Google Scholar, 6Sawicki P.T. Dahne R. Bender R. Berger M. Diabetologia. 1996; 39: 77-81PubMed Google Scholar, 7Veglio M. Bruno G. Borra M. Macchia G. Bargero G. D'Errico N. Pagano G.F. Cavallo-Perin P. J. Intern. Med. 2002; 251: 317-324Crossref PubMed Scopus (102) Google Scholar, 8Cardoso C.R. Salles G.F. Deccache W. Stroke. 2003; 34: 2187-2194Crossref PubMed Scopus (44) Google Scholar). Our recent study revealed that the long QT syndrome gene, human ether-a-go-go-related gene (HERG) encoding the channel responsible for rapid delayed rectifier K+ current (IKr), is significantly down-regulated in its expression in diabetic hearts and this down-regulation contributes critically to diabetic repolarization slowing and QT prolongation (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar). Strikingly, HERG expressions at transcriptional and post-transcriptional levels diverge in diabetic hearts, with its protein levels being reduced by some 60% while the mRNA levels remaining essentially unaltered (10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar). These disparate changes indicate that HERG expression is impaired mainly at the post-transcriptional level; however, it remained unclear what are the determinants for the differential regulations of HERG expression at protein and transcript levels. MicroRNAs (miRNAs) are endogenous ∼22-nucleotide non-coding RNAs that anneal to inexactly complementary sequences in the 3′-untranslated regions of target mRNAs of protein-coding genes to regulate gene expression. The major characteristics of miRNA actions is to specify translational repression without affecting the levels of the targeted mRNA (11Ambros V. Nature. 2004; 431: 350-355Crossref PubMed Scopus (9135) Google Scholar, 12Brennecke J. Stark A. Russell R.B. Cohen S.M. PLoS Biol. 2005; 3: e85Crossref PubMed Scopus (1863) Google Scholar). Among >300 miRNAs identified thus far, miR-1 and miR-133 are known to specifically express in adult cardiac and skeletal muscle tissues (13Zhao Y. Samal E. Srivastava D. Nature. 2005; 436: 214-220Crossref PubMed Scopus (1370) Google Scholar, 14Chen J.F. Mandel E.M. Thomson J.M. Wu Q. Callis T.E. Hammond S.M. Conlon F.L. Wang D.Z. Nat. Genet. 2006; 38: 228-233Crossref PubMed Scopus (2254) Google Scholar). Recent studies revealed that miR-1 and miR-133 play critical roles in regulating myogenesis. Increasing expression of miR-1 and miR-133 has been found in neonatal hearts and substantially higher levels are maintained in adult cardiac tissues (14Chen J.F. Mandel E.M. Thomson J.M. Wu Q. Callis T.E. Hammond S.M. Conlon F.L. Wang D.Z. Nat. Genet. 2006; 38: 228-233Crossref PubMed Scopus (2254) Google Scholar), suggesting that in addition to regulating myogenesis, they may also possess other cellular functions in adult cardiac cells. However, our current understanding of the function of these miRNAs is still limited to developmental regulation and their possible roles in other cellular processes have not yet been explored. We proposed that the muscle-specific miRNAs miR-1/miR-133 are able to repress HERG translation while keeping its mRNA unaffected and their levels are up-regulated in diabetic hearts, which causes the disparate changes of HERG protein and mRNA levels. This study was designed to test this hypothesis. Preparation of Rabbit Model of DM—Male New Zealand White rabbits weighing 1.6∼2.0 kg (Charles River Canada Inc.) were used and the procedures for development of alloxan-induced DM model were the same as previously described in detail (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar). The QT measurements and simultaneously recorded RR intervals were used to derive heart rate corrected QT intervals. Incidences of ventricular tachycardia and ventricular fibrillation were determined. All procedures are in accordance with the guidelines set by the Animal Ethics Committee of the Montreal Heart Institute and of Harbin Medical University. Isolation of Rabbit Ventricular Myocytes and Cell Culture—Myocytes were isolated from rabbit left ventricular endocardium via enzymatic digestion of the whole heart on a Langendorff apparatus with the procedures similar to previously described (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar). The freshly isolated myocytes were stored either in the extracellular solution for patch clamp recordings or in 199 Medium as detailed elsewhere (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 15Wang Z. Feng J. Shi H. Pond A. Nerbonne J.M. Nattel S. Circ. Res. 1999; 84: 551-561Crossref PubMed Scopus (178) Google Scholar). Whole-cell Patch Clamp Recording—Patch clamp recording of IKr currents has been described in detail elsewhere (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar). Synthesis of miRNAs and Anti-miRNA Antisense Inhibitors and Their Mutant Constructs—miR-1 and miR-133 and their respective mutant constructs were synthesized by Integrated DNA Technologies, Inc. as detailed elsewhere (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar) (also see supplemental Fig. 1). The mutant miRNAs each had eight nucleotides mismatches at the 5′-end, which disrupts their binding to the target sites and thus turns the miRNAs into negative controls (11Ambros V. Nature. 2004; 431: 350-355Crossref PubMed Scopus (9135) Google Scholar, 12Brennecke J. Stark A. Russell R.B. Cohen S.M. PLoS Biol. 2005; 3: e85Crossref PubMed Scopus (1863) Google Scholar, 13Zhao Y. Samal E. Srivastava D. Nature. 2005; 436: 214-220Crossref PubMed Scopus (1370) Google Scholar, 14Chen J.F. Mandel E.M. Thomson J.M. Wu Q. Callis T.E. Hammond S.M. Conlon F.L. Wang D.Z. Nat. Genet. 2006; 38: 228-233Crossref PubMed Scopus (2254) Google Scholar, 16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar). Construction of Chimeric miRNA-Target Site-Luciferase Reporter Vectors—To construct reporter vectors bearing miRNA-target sites, we synthesized (by Invitrogen) fragments containing the exact target sites for miR-1 and miR-133 or the mutated target sites, HERG cDNA, and inserted these fragments into the multiple cloning sites downstream the luciferase gene (HindIII and SpeI sites) in the pMIR-REPORT™ luciferase miRNA expression reporter vector (Ambion, Inc.), as detailed elsewhere (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar). Small Interference RNA (siRNA) Treatment—The Stealth™ siRNAs targeting serum response factor (SRF) (sense: 5′-GCAGAGGCAACUGACUUCAUUUGUG-3′ and antisense: 5′-CACAAAUGAAGUCAGUUGCCUCUGC-3′; 3096–3131) and a negative control siRNA (sense: 5′-GCAACGGGUCAUUCAUUACUAGGUG-3′ and antisense: 5′-CACCUAGUAAUGAAUGACCCGUUGC-3′; 3096–3131) were synthesized by Invitrogen. Cell Culture—SKBr3 (human breast cancer cell line) and HEK293 (human embryonic kidney cell line) were purchased from ATCC (Manassas, VA). The cells were cultured as described previously (17Wang H. Zhang Y. Cao L. Han H. Wang J. Yang B. Nattel S. Wang Z. Cancer Res. 2002; 62: 4843-4848PubMed Google Scholar). Transfection and Luciferase Assay—The transfection procedures for cell lines and rabbit cardiac myocytes in primary culture, and luciferase activity assays were the same as described in detail elsewhere (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar, 17Wang H. Zhang Y. Cao L. Han H. Wang J. Yang B. Nattel S. Wang Z. Cancer Res. 2002; 62: 4843-4848PubMed Google Scholar). Before transfection, cells were starved to synchronize growth by incubating in serum- and antibiotic-free medium for 12 h. Quantification of mRNA and miRNA Levels—The procedures for quantification of HERG and SRF transcripts by conventional TaqMan real-time RT-PCR were the same as described previously (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar). The mirVana™ qRT-PCR miRNA detection kit (Ambion), a quantitative reverse transcription (qRT)-PCR kit, was used in conjunction with real-time PCR with SYBR Green I for quantification of miR-1 and miR-133 (miR-133a + miR-133b) transcripts (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar). The total RNA samples were isolated with Ambion's mirVana miRNA isolation kit from SKBr3 cells, HEK293 cells, rabbit hearts, and human hearts. Fold variations in expression of miR-133 between RNA samples were calculated after normalization to 5s rRNA. Human tissues were obtained from the Second Affiliated Hospital of Harbin Medical University under the procedures approved by the Ethnic Committee for Use of Human Samples of the Harbin Medical University and from the Réseau de tissus pour études biologiques (RETEB) tissue bank under the procedures approved by the Human Research Ethics Committee of the Montreal Heart Institute. The criteria for inclusion of the tissues in our study were the patients that did not have primary heart problems at the time of death. Western Blot—The procedures for semi-quantification of ERG and SRF protein levels were the same as described in detail elsewhere (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar, 15Wang Z. Feng J. Shi H. Pond A. Nerbonne J.M. Nattel S. Circ. Res. 1999; 84: 551-561Crossref PubMed Scopus (178) Google Scholar, 16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar, 17Wang H. Zhang Y. Cao L. Han H. Wang J. Yang B. Nattel S. Wang Z. Cancer Res. 2002; 62: 4843-4848PubMed Google Scholar). Membrane protein samples were extracted from left ventricular wall of rabbits and SKBr3 cells. The goat polyclonal antibodies against ERG and SRF were both purchased from Santa Cruz Biotechnology Inc. Data Analysis—Group data are expressed as mean ± S.E. Statistical comparisons (performed using analysis of variance followed by Dunnett's method) were carried out using Microsoft Excel. A two-tailed p < was to indicate a of miR-1 and miR-133 and of ERG in miR-1 and miR-133 were expressed in rabbit however, miR-133 was that of The levels of both miR-1 and miR-133 were found some and in the ventricular RNA samples from rabbits with DM from control of the muscle-specific miRNAs was also in the ventricular samples from DM patients 1). We also the in our study (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar), the protein level of the rabbit ERG was significantly in diabetic hearts in hearts that the transcript level remained We the same between HERG protein and mRNA expression levels in the hearts from DM patients 1). that the of ERG in rabbit and and human and were presumably to in the the and the the of ERG protein (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar). The is with our (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar) and that of HERG is to the by E.M. Wang J. S.A. J. Biol. 2004; PDF PubMed Scopus Google Scholar). Repression of HERG by and in their We identified multiple target sites for miR-133 in and in HERG on at nucleotides the nucleotides from the of miR-133 Fig. 1). These sites may to the regulation by HERG sites with complementary nucleotides to that HERG and are the of miR-133 for post-transcriptional we first inserted HERG into the 3′-untranslated of a luciferase reporter containing a to the of miR-133 on reporter expression. of miR-133 and the vector into HEK293 cells luciferase to transfection of the but of the mutant miR-133 to HEK293 cells were used for luciferase reporter assays because these cells not express endogenous ERG protein and miR-1/miR-133 Fig. of miR-133 with its antisense the silencing effect on luciferase reporter (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar, J. N. R. M. M. Nature. 2005; PubMed Scopus Google Scholar, J. Res. 2005; PubMed Scopus Google Scholar). an negative of miR-1 to luciferase reporter The and of miRNAs was by using miR-1 and miR-133 in which the complementary sequences of miR-1 and miR-133 were downstream of luciferase gene in the We the of miR-133 on endogenous expression of HERG at the protein level by Western with SKBr3 protein SKBr3 was used because it is a human cell that endogenous HERG (17Wang H. Zhang Y. Cao L. Han H. Wang J. Yang B. Nattel S. Wang Z. Cancer Res. 2002; 62: 4843-4848PubMed Google Scholar) but not express the muscle-specific miR-1 or miR-133 Fig. Our data that transfection of miR-133 reduced HERG protein level to of control and as a negative control the mutant miR-133 did not changes of the of miR-133, the of the miR-133 transfection of miR-1 to HERG protein miR-133 produced on HERG mRNA level that miR-133 not HERG mRNA The of ERG regulation by miR-133 was by patch clamp studies of IKr in isolated ventricular myocytes in primary IKr in the myocytes from DM hearts or in the myocytes from control heart with miR-133 was severely The depression by DM was by and that by exogenous miR-133 was by IKr in control cells, presumably by the of endogenous a negative miR-1 to of SRF in miR-133 has been that expression of is binding of SRF to their regions (13Zhao Y. Samal E. Srivastava D. Nature. 2005; 436: 214-220Crossref PubMed Scopus (1370) Google Scholar, 14Chen J.F. Mandel E.M. Thomson J.M. Wu Q. Callis T.E. Hammond S.M. Conlon F.L. Wang D.Z. Nat. Genet. 2006; 38: 228-233Crossref PubMed Scopus (2254) Google Scholar), an transcriptional factor in cardiac cells G. L. H. J. A Biol. Med. 53: PubMed Scopus Google Scholar, R. Xiao Q. J. 2005; 39: PDF PubMed Scopus Google Scholar, X. G. J. P. Yang J. J. Am. J. Physiol. 2001; PubMed Google Scholar, J. Biol. 1996; PDF PubMed Scopus Google Scholar). SRF protein level was found significantly increased in diabetic hearts to hearts and was SRF transcript level of the DM myocytes in primary with which has been to binding of SRF to its A. L. Biochem. PubMed Scopus Google Scholar), the in miR-1/miR-133 expression This effect was by silencing of SRF using the siRNA against SRF in cells isolated from DM SRF-siRNA, but not the negative control increased IKr The siRNA and A both increased IKr in control cells, presumably by The of the in silencing SRF expression at mRNA level was the primary did not for of protein samples for Western analysis of SRF protein levels or HERG protein levels. gene regulation is a of that at the post-transcriptional However, our to have not been or for of the which has the functions of miRNAs. Our current understanding of the functions of miRNAs on their or developmental expression as as their and is thus limited to and and function are major to in miRNA The study revealed the of a miRNA to regulate channel expression and the possible role in electrical in diabetic thus expanded our understanding of the cellular function and pathophysiological roles of miRNAs in a the that miRNAs likely have functions in the cells. Our study an for the between changes of expression at protein and mRNA levels. our recent study on QT prolongation of diabetic hearts, we that IKr and ERG protein level were being the major factor for QT prolongation in diabetic while ERG mRNA level was unaffected (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar). of IKr to expression repression of HERG by miR-133 is to in repolarization slowing thereby QT our recent we found that miR-133 (16Luo X. Lin H. Lu Y. Li B. Xiao J. Yang B. Wang Z. J. Cell Physiol. 2007; (in press)Google Scholar), a channel protein responsible for the delayed rectifier K+ current in cardiac cells. However, has to diabetic QT prolongation is still an and our studies a role of (9Zhang Y. Lin H. Xiao J. Bai Y.L. Wang J. Zhang H. Yang B. Wang Z. Cell Physiol. Biochem. 2007; 19: 225-238Crossref PubMed Scopus (57) Google Scholar, 10Zhang Y. Wang J. Bai Y. Zhang H. Yang B. Wang H. Wang Z. Am. J. Physiol. 2006; 291: 1446-1455Crossref PubMed Scopus (86) Google Scholar). our study to an role of miR-133 in QT prolongation in diabetes and in other pathological as Our data also indicate that the miR-1 is not responsible for the down-regulation of IKr in DM is to here that the of disparate changes of ERG expression at protein and mRNA levels have also been in heart and studies found that IKr current was significantly in myocytes from hearts that is also by repolarization slowing and QT prolongation similar to diabetic hearts, that the mRNA level of HERG was under these J. Biol. 1996; PDF PubMed Scopus Google Scholar, A. L. Biochem. PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar, Res. Scopus Google Scholar, A. Nattel S. Am. J. Physiol. 2002; PubMed Scopus Google Scholar, Y. W. Lu Z. Res. 2000; PubMed Scopus Google Scholar). these disparate changes of ERG protein and mRNA in hearts and are consequent to of miR-133 expression is of detailed Our study also evidence for the role of SRF in miR-133 overexpression in DM The not the in miR-133 but also depressed IKr in SRF inhibition or have on diabetic QT prolongation We Yang for and for human with

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Revue

Journal of Biological Chemistry

Thématique

MicroRNA in disease regulation

Domaine

Biochemistry, Genetics and Molecular Biology

Établissements canadiens

Université de MontréalMontreal Heart Institute

Organismes subventionnaires

National Natural Science Foundation of China

Mots-clés

hERGGene silencingmicroRNATransactivationErgBiologyGene expressionMessenger RNAPsychological repressionRegulation of gene expressionEndocrinologyInternal medicineGene knockdownRNA interferenceCell biologyMolecular biologyGenePotassium channelGeneticsMedicineRNANeuroscience

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