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miR-448 regulates potassium voltage-gated channel subfamily A member 4 (KCNA4) in ischemia and heart failure

Published:January 21, 2023DOI:https://doi.org/10.1016/j.hrthm.2023.01.021

      Abstract

      Background

      MicroRNA ,miR-448, mediates some of the effects of ischemia on arrhythmic risk. Potassium Voltage-gated Channel Subfamily A Member 4 (KCNA4) encodes a Kv1.4 current that opens in response to membrane depolarization and is essential for regulating action potential duration in heart. KCNA4 has a miR-448 binding site.

      Objective

      Therefore, we investigated whether miR-448 was involved in the regulation of KCNA4 mRNA expression in ischemia.

      Methods

      Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of KCNA4 and miR-448. Pull-down assays were used to examine the interaction between miR-448 and KCNA4. A miR-448 decoy and binding site mutation were used to examine specificity of the effect for KCNA4.

      Results

      The expression of KCNA4 is diminished in ischemia and human HF tissues with ventricular tachycardia. Previously, we have shown miR-448 is upregulated in ischemia, and inhibition can prevent arrhythmic risk after myocardial infarction. The 3'-UTR of KCNA4 has a conserved miR-448 binding site. MiR-448 bound to this site directly and reduced KCNA4 expression and the transient outward potassium current (Ito). Inhibition of miR-448 restored KCNA4.

      Conclusion

      These findings showed a link between Kv1.4 downregulation and miR-448-mediated upregulation in ischemia, suggesting a new mechanism for the antiarrhythmic effect of miR-448 inhibition.

      Keywords

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      References

        • Ghuran A.V.
        • Camm A.J.
        Ischaemic heart disease presenting as arrhythmias.
        Br Med Bull. 2001; 59: 193-210
      1. Glancy DL, Atluri P, Rodriguez JF, Subramaniam PN. Cardiac arrhythmias during myocardial infarction. Proc (Bayl Univ Med Cent). Vol 282015:192-193.

        • Kang G.J.
        • Xie A.
        • Liu H.
        • Dudley S.C.
        MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel.
        JCI Insight. Dec 2020; : 5
        • Zhou A.
        • Shi G.
        • Kang G.J.
        • Xie A.
        • Liu H.
        • Jiang N.
        • Liu M.
        • Jeong E.M.
        • Dudley S.C.
        RNA Binding Protein, HuR, Regulates SCN5A Expression Through Stabilizing MEF2C transcription factor mRNA.
        J Am Heart Assoc Apr. 2018; 7
        • Zhou A.
        • Xie A.
        • Kim T.Y.
        • Liu H.
        • Shi G.
        • Kang G.J.
        • Jiang N.
        • Liu M.
        • Jeong E.M.
        • Choi B.R.
        • Dudley S.C.
        HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure.
        Heart Rhythm Jul. 2018; 15: 1072-1080
        • Gao G.
        • Dudley S.C.
        RBM25/LUC7L3 function in cardiac sodium channel splicing regulation of human heart failure.
        Trends Cardiovasc Med Jan. 2013; 23: 5-8
        • Shang L.L.
        • Pfahnl A.E.
        • Sanyal S.
        • Jiao Z.
        • Allen J.
        • Banach K.
        • Fahrenbach J.
        • Weiss D.
        • Taylor W.R.
        • Zafari A.M.
        • Dudley S.C.
        Human heart failure is associated with abnormal C-terminal splicing variants in the cardiac sodium channel.
        Circ Res Nov. 2007; 101: 1146-1154
      2. Wymore RS, Negulescu D, Kinoshita K, Kalman K, Aiyar J, Gutman GA, Chandy KG. Characterization of the transcription unit of mouse Kv1.4, a voltage-gated potassium channel gene. J Biol Chem Jun 28 1996;271:15629-15634.

      3. Wymore RS, Korenberg JR, Kinoshita KD, Aiyar J, Coyne C, Chen XN, Hustad CM, Copeland NG, Gutman GA, Jenkins NA. Genomic organization, nucleotide sequence, biophysical properties, and localization of the voltage-gated K+ channel gene KCNA4/Kv1.4 to mouse chromosome 2/human 11p14 and mapping of KCNC1/Kv3.1 to mouse 7/human 11p14.3-p15.2 and KCNA1/Kv1.1 to human 12p13. Genomics Mar 15 1994;20:191-202.

        • Kabakov A.Y.
        • Sengun E.
        • Lu Y.
        • Roder K.
        • Bronk P.
        • Baggett B.
        • Turan N.N.
        • Moshal K.S.
        • Koren G.
        Three-Week-Old Rabbit Ventricular Cardiomyocytes as a Novel System to Study Cardiac Excitation and EC Coupling.
        Front Physiol. 2021; 12672360
        • Hong J.
        • Fu S.
        • Gao L.
        • Cai Y.
        • Lazartigues E.
        • Wang H.J.
        Voltage-gated potassium channel dysfunction in dorsal root ganglia contributes to the exaggerated exercise pressor reflex in rats with chronic heart failure.
        Am J Physiol Heart Circ Physiol Aug 1. 2021; 321: H461-h474
        • Kilfoil P.J.
        • Chapalamadugu K.C.
        • Hu X.
        • Zhang D.
        • Raucci Jr., F.J.
        • Tur J.
        • Brittian K.R.
        • Jones S.P.
        • Bhatnagar A.
        • Tipparaju S.M.
        • Nystoriak M.A.
        Metabolic regulation of Kv channels and cardiac repolarization by Kvβ2 subunits.
        J Mol Cell Cardiol Dec. 2019; 137: 93-106
        • Wickenden A.D.
        • Jegla T.J.
        • Kaprielian R.
        • Backx P.H.
        Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K+ current in rat ventricle.
        Am J Physiol May. 1999; 276: H1599-1607
        • London B.
        • Wang D.W.
        • Hill J.A.
        • Bennett P.B.
        The transient outward current in mice lacking the potassium channel gene Kv1.4.
        J Physiol May 15. 1998; 509: 171-182
        • Dixon J.E.
        • Shi W.
        • Wang H.S.
        • McDonald C.
        • Yu H.
        • Wymore R.S.
        • Cohen I.S.
        • McKinnon D.
        Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current.
        Circ Res Oct. 1996; 79: 659-668
        • Tamkun M.M.
        • Knoth K.M.
        • Walbridge J.A.
        • Kroemer H.
        • Roden D.M.
        • Glover D.M.
        Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle.
        Faseb j Mar 1. 1991; 5: 331-337
        • Mahrouf-Yorgov M.
        • Augeul L.
        • Da Silva C.C.
        • et al.
        Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties.
        Cell Death Differ Jul. 2017; 24: 1224-1238
        • Orozco P.
        • Montoya Y.
        • Bustamante J.
        Development of endomyocardial fibrosis model using a cell patterning technique: In vitro interaction of cell coculture of 3T3 fibroblasts and RL-14 cardiomyocytes.
        PLoS One. 2020; 15e0229158
        • Alammari A.H.
        • Shoieb S.M.
        • Maayah Z.H.
        • El-Kadi A.O.S.
        Fluconazole represses cytochrome P450 1B1 and its associated arachidonic acid metabolites in the heart and protects against angiotensin II-induced cardiac hypertrophy.
        J Pharm Sci Jul. 2020; 109: 2321-2335
        • Xie A.
        • Zhou A.
        • Liu H.
        • Shi G.
        • Liu M.
        • Boheler K.R.
        • Dudley S.C.
        Mitochondrial Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes.
        PLoS One. 2018; 13e0200448
        • Ma J.
        • Guo L.
        • Fiene S.J.
        • Anson B.D.
        • Thomson J.A.
        • Kamp T.J.
        • Kolaja K.L.
        • Swanson B.J.
        • January C.T.
        High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents.
        Am J Physiol Heart Circ Physiol Nov. 2011; 301: H2006-2017
        • Cubeddu L.X.
        Drug-induced inhibition and trafficking disruption of ion channels: pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias.
        Curr Cardiol Rev. 2016; 12: 141-154
        • Veerman C.C.
        • Verkerk A.O.
        • Blom M.T.
        • Klemens C.A.
        • Langendijk P.N.
        • van Ginneken A.C.
        • Wilders R.
        • Tan H.L.
        Slow delayed rectifier potassium current blockade contributes importantly to drug-induced long QT syndrome.
        Circ Arrhythm Electrophysiol. Oct 2013; 6: 1002-1009
      4. Gräni C, Benz DC, Gupta S, Windecker S, Kwong RY. Sudden cardiac death in ischemic heart disease: from imaging arrhythmogenic substrate to guiding therapies. JACC Cardiovasc Imaging 10 2020;13:2223-2238.

        • Jagu B.
        • Charpentier F.
        • Toumaniantz G.
        Identifying potential functional impact of mutations and polymorphisms: linking heart failure, increased risk of arrhythmias and sudden cardiac death.
        Front Physiol Sep. 20 2013; 4: 254
      5. Liu M, Liu H, Parthiban P, Kang GJ, Shi G, Feng F, Zhou A, Gu L, Karnopp C, Tolkacheva EG, Dudley SC. Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction. J Clin Invest 09 15 2021;131.

        • Sticht C.
        • De La Torre C.
        • Parveen A.
        • Gretz N.
        miRWalk: An online resource for prediction of microRNA binding sites.
        PLoS One. 2018; 13e0206239
        • Suzuki S.
        • Satoh T.
        • Yasuoka H.
        • Hamaguchi Y.
        • Tanaka K.
        • Kawakami Y.
        • Suzuki N.
        • Kuwana M.
        Novel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis.
        J Neuroimmunol. Dec 30 2005; 170: 141-149
        • Gao X.
        • Yu S.
        • Guan Y.
        • Shen Y.
        • Xu L.
        Nucleoporin 50 mediates KCNA4 transcription to regulate cardiac electrical activity.
        J Cell Sci 09. 2021; 15: 134
        • Nishiyama A.
        • Ishii D.N.
        • Backx P.H.
        • Pulford B.E.
        • Birks B.R.
        • Tamkun M.M.
        Altered K+ channel gene expression in diabetic rat ventricle: isoform switching between Kv4.2 and Kv1.4.
        Am J Physiol Heart Circ Physiol Oct. 2001; 281: H1800-1807
        • Dixon J.E.
        • McKinnon D.
        Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats.
        Circ Res Aug. 1994; 75: 252-260