Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes

详细信息    查看全文

• 作者：J. S. Schulte ; E. Fehrmann ; M. A. Tekook ; D. Kranick…
• 关键词：Transcription factor CREM ; Arrhythmia ; Remodeling ; NCX
• 刊名：Basic Research in Cardiology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：111
• 期：2
• 全文大小：1,555 KB
• 参考文献：1.Adabag AS, Luepker RV, Roger VL, Gersh BJ (2010) Sudden cardiac death: epidemiology and risk factors. Nat Rev Cardiol 7:216–225. doi:10.​1038/​nrcardio.​2010.​3 CrossRef PubMed
  2.Altarejos JY, Montminy M (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12:141–151. doi:10.​1038/​nrm3072 PubMedCentral CrossRef PubMed
  3.Ataklte F, Erqou S, Laukkanen J, Kaptoge S (2013) Meta-analysis of ventricular premature complexes and their relation to cardiac mortality in general populations. Am J Cardiol 112:1263–1270. doi:10.​1016/​j.​amjcard.​2013.​05.​065 CrossRef PubMed
  4.Bai Y, Jones PP, Guo J, Zhong X, Clark RB, Zhou Q, Wang R, Vallmitjana A, Benitez R, Hove-Madsen L, Semeniuk L, Guo A, Song L, Duff HJ, Chen SRW (2013) Phospholamban knockout breaks arrhythmogenic Ca2+ waves and suppresses catecholaminergic polymorphic ventricular tachycardia in mice. Circ Res 113:517–526. doi:10.​1161/​CIRCRESAHA.​113.​301678 CrossRef PubMed
  5.Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49. doi:10.​1146/​annurev.​physiol.​70.​113006.​100455 CrossRef PubMed
  6.Bögeholz N, Pauls P, Bauer BK, Schulte JS, Dechering DG, Frommeyer G, Kirchhefer U, Goldhaber JI, Müller FU, Eckardt L, Pott C (2015) Suppression of early and late afterdepolarizations by heterozygous knockout of the Na+/Ca2+ exchanger in a murine model. Circ Arrhythm Electrophysiol. doi:10.​1161/​CIRCEP.​115.​002927 PubMed
  7.Chelu MG, Sarma S, Sood S, Wang S, van Oort RJ, Skapura DG, Li N, Santonastasi M, Müller FU, Schmitz W, Schotten U, Anderson ME, Valderrábano M, Dobrev D, Wehrens XH (2009) Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. J Clin Invest 119:1940–1951. doi:10.​1172/​JCI37059 PubMedCentral PubMed
  8.Cutler MJ, Wan X, Plummer BN, Liu H, Deschenes I, Laurita KR, Hajjar RJ, Rosenbaum DS (2012) Targeted sarcoplasmic reticulum Ca2+ ATPase 2a gene delivery to restore electrical stability in the failing heart. Circulation 126:2095–2104. doi:10.​1161/​CIRCULATIONAHA.​111.​071480 PubMedCentral CrossRef PubMed
  9.Deshmukh A, Barnard J, Sun H, Newton D, Castel L, Pettersson G, Johnston D, Roselli E, Gillinov AM, McCurry K, Moravec C, Smith JD, van Wagoner DR, Chung MK (2015) Left atrial transcriptional changes associated with atrial fibrillation susceptibility and persistence. Circ Arrhythm Electrophysiol 8:32–41. doi:10.​1161/​CIRCEP.​114.​001632 CrossRef PubMed
  10.Ding B, Abe J, Wei H, Huang Q, Walsh RA, Molina CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C (2005) Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure. Circulation 111:2469–2476. doi:10.​1161/​01.​CIR.​0000165128.​39715.​87 PubMedCentral CrossRef PubMed
  11.(1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353:2001–2007. doi:10.​1016/​S0140-6736(99)04440-2
  12.Guo W (2002) Role of heteromultimers in the generation of myocardial transient outward K+ currents. Circ Res 90:586–593. doi:10.​1161/​01.​RES.​0000012664.​05949.​E0 CrossRef PubMed
  13.Hjalmarson Å, Fagerberg B (2000) MERIT-HF mortality and morbidity data. Basic Res Cardiol 95:I98–I103. doi:10.​1007/​s003950070017 CrossRef PubMed
  14.Ito K, Yan X, Tajima M, Su Z, Barry WH, Lorell BH (2000) Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts. Circ Res 87:588–595. doi:10.​1161/​01.​RES.​87.​7.​588 CrossRef PubMed
  15.Kannel WB, Plehn JF, Cupples L (1988) Cardiac failure and sudden death in the Framingham Study. Am Heart J 115:869–875. doi:10.​1016/​0002-8703(88)90891-5 CrossRef PubMed
  16.Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD (1995) Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 26:1257–1263. doi:10.​1016/​0735-1097(95)00332-0 CrossRef PubMed
  17.Kirchhof P, Marijon E, Fabritz L, Li N, Wang W, Wang T, Schulte K, Hanstein J, Schulte JS, Vogel M, Mougenot N, Laakmann S, Fortmueller L, Eckstein J, Verheule S, Kaese S, Staab A, Grote-Wessels S, Schotten U, Moubarak G, Wehrens Xander H T, Schmitz W, Hatem S, Müller FU (2013) Overexpression of cAMP-response element modulator causes abnormal growth and development of the atrial myocardium resulting in a substrate for sustained atrial fibrillation in mice. Int J Cardiol 166:366–374. doi:10.​1016/​j.​ijcard.​2011.​10.​057 CrossRef PubMed
  18.Li N, Chiang DY, Wang S, Wang Q, Sun L, Voigt N, Respress JL, Ather S, Skapura DG, Jordan VK, Horrigan FT, Schmitz W, Müller FU, Valderrabano M, Nattel S, Dobrev D, Wehrens XHT (2014) Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model. Circulation 129:1276–1285. doi:10.​1161/​CIRCULATIONAHA.​113.​006611 PubMedCentral CrossRef PubMed
  19.Lohse MJ, Engelhardt S, Eschenhagen T (2003) What is the role of beta-adrenergic signaling in heart failure? Circ Res 93:896–906. doi:10.​1161/​01.​RES.​0000102042.​83024.​CA CrossRef PubMed
  20.Maczewski M, Mackiewicz U (2008) Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart. Cardiovasc Res 79:42–51. doi:10.​1093/​cvr/​cvn057 CrossRef PubMed
  21.Mani SK, Egan EA, Addy BK, Grimm M, Kasiganesan H, Thiyagarajan T, Renaud L, Brown JH, Kern CB, Menick DR (2010) beta-Adrenergic receptor stimulated Ncx1 upregulation is mediated via a CaMKII/AP-1 signaling pathway in adult cardiomyocytes. J Mol Cell Cardiol 48:342–351. doi:10.​1016/​j.​yjmcc.​2009.​11.​007 PubMedCentral CrossRef PubMed
  22.Menick DR, Li MS, Chernysh O, Renaud L, Kimbrough D, Kasiganesan H, Mani SK (2013) Transcriptional pathways and potential therapeutic targets in the regulation of Ncx1 expression in cardiac hypertrophy and failure. Adv Exp Med Biol 961:125–135. doi:10.​1007/​978-1-4614-4756-6_​11 PubMedCentral CrossRef PubMed
  23.Meredith IT, Broughton A, Jennings GL, Esler MD (1991) Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias. N Engl J Med 325:618–624. doi:10.​1056/​NEJM199108293250​905 CrossRef PubMed
  24.Molina CA, Foulkes NS, Lalli E, Sassone-Corsi P (1993) Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell 75:875–886. doi:10.​1016/​0092-8674(93)90532-U CrossRef PubMed
  25.Müller FU, Bokník P, Knapp J, Neumann J, Vahlensieck U, Oetjen E, Scheld HH, Schmitz W (1998) Identification and expression of a novel isoform of cAMP response element modulator in the human heart. FASEB J 12:1191–1199PubMed
  26.Müller FU, Lewin G, Matus M, Neumann J, Riemann B, Wistuba J, Schütz G, Schmitz W (2003) Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene. FASEB J 17:103–105. doi:10.​1096/​fj.​02-0486fje PubMed
  27.Müller FU, Lewin G, Baba HA, Bokník P, Fabritz L, Kirchhefer U, Kirchhof P, Loser K, Matus M, Neumann J, Riemann B, Schmitz W (2005) Heart-directed expression of a human cardiac isoform of cAMP-response element modulator in transgenic mice. J Biol Chem 280:6906–6914. doi:10.​1074/​jbc.​M407864200 CrossRef PubMed
  28.Myers R, Timofeyev V, Li N, Kim C, Ledford HA, Sirish P, Lau V, Zhang Y, Fayyaz K, Singapuri A, Lopez JE, Knowlton AA, Zhang X, Chiamvimonvat N (2015) Feedback mechanisms for cardiac-specific microRNAs and cAMP signaling in electrical remodeling. Circ Arrhythm Electrophysiol 8:942–950. doi:10.​1161/​CIRCEP.​114.​002162 CrossRef PubMed
  29.Myles RC, Wang L, Kang C, Bers DM, Ripplinger CM (2012) Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia. Circ Res 110:1454–1464. doi:10.​1161/​CIRCRESAHA.​111.​262345 PubMedCentral CrossRef PubMed
  30.Nass RD, Aiba T, Tomaselli GF, Akar FG (2008) Mechanisms of disease: ion channel remodeling in the failing ventricle. Nat Clin Pract Cardiovasc Med 5:196–207. doi:10.​1038/​ncpcardio1130 CrossRef PubMed
  31.Neef S, Maier LS (2013) Novel aspects of excitation-contraction coupling in heart failure. Basic Res Cardiol 108:360. doi:10.​1007/​s00395-013-0360-2 CrossRef PubMed
  32.Pott C, Muszynski A, Ruhe M, Bögeholz N, Schulte JS, Milberg P, Mönnig G, Fabritz L, Goldhaber JI, Breithardt G, Schmitz W, Philipson KD, Eckardt L, Kirchhof P, Müller FU (2012) Proarrhythmia in a non-failing murine model of cardiac-specific Na+/Ca2+ exchanger overexpression: whole heart and cellular mechanisms. Basic Res Cardiol 107:247. doi:10.​1007/​s00395-012-0247-7 PubMedCentral CrossRef PubMed
  33.Rubart M (2005) Mechanisms of sudden cardiac death. J Clin Invest 115:2305–2315. doi:10.​1172/​JCI26381 PubMedCentral CrossRef PubMed
  34.Schulte JS, Seidl MD, Nunes F, Freese C, Schneider M, Schmitz W, Müller FU (2012) CREB critically regulates action potential shape and duration in the adult mouse ventricle. Am J Physiol Heart Circ Physiol 302:H1998–H2007. doi:10.​1152/​ajpheart.​00057.​2011 CrossRef PubMed
  35.Schulte JS, Seidl MD, Muller FU (2014) The role of transcription factors in the formation of an arrhythmogenic substrate in congestive human heart failure. Curr Med Chem 21:1281–1298. doi:10.​2174/​0929867311320999​0172 CrossRef PubMed
  36.Seidl MD, Nunes F, Fels B, Hildebrandt I, Schmitz W, Schulze-Osthoff K, Müller FU (2014) A novel intronic promoter of the Crem gene induces small ICER (smICER) isoforms. FASEB J 28:143–152. doi:10.​1096/​fj.​13-231977 CrossRef PubMed
  37.Sipido K (2002) Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res 53:782–805. doi:10.​1016/​S0008-6363(01)00470-9 CrossRef PubMed
  38.Vandesompele J, de Preter K, Pattyn F, Poppe B, van Roy N, de Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(RESEARCH0034):1. doi:10.​1186/​gb-2002-3-7-research0034
  39.Wang Y, Hill JA (2010) Electrophysiological remodeling in heart failure. J Mol Cell Cardiol 48:619–632. doi:10.​1016/​j.​yjmcc.​2010.​01.​009 PubMedCentral CrossRef PubMed
  40.Xu H, Barry DM, Li H, Brunet S, Guo W, Nerbonne JM (1999) Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 subunit. Circ Res 85:623–633. doi:10.​1161/​01.​RES.​85.​7.​623 CrossRef PubMed
  41.Zhang X, Ai X, Nakayama H, Chen B, Harris DM, Tang M, Xie Y, Szeto C, Li Y, Li Y, Zhang H, Eckhart AD, Koch WJ, Molkentin JD, Chen X (2016) Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias. Basic Res Cardiol 111:4. doi:10.​1007/​s00395-015-0523-4 CrossRef PubMed
  42.Zhou J, Kodirov S, Murata M, Buckett PD, Nerbonne JM, Koren G (2003) Regional upregulation of Kv2.1-encoded current, IK, slow2, in Kv1DN mice is abolished by crossbreeding with Kv2DN mice. Am J Physiol Heart Circ Physiol 284:H491–H500. doi:10.​1152/​ajpheart.​00576.​2002 CrossRef PubMed
  
• 作者单位：J. S. Schulte (1)
  E. Fehrmann (1)
  M. A. Tekook (1)
  D. Kranick (1)
  B. Fels (1)
  N. Li (2)
  X. H. T. Wehrens (2)
  A. Heinick (1)
  M. D. Seidl (1)
  W. Schmitz (1)
  F. U. Müller (1)
  
  1. Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, 48149, Münster, Germany
  2. Department of Molecular Physiology and Biophysics, Medicine (Cardiology), and Pediatrics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Cardiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1435-1803

文摘

Chronic β-adrenergic stimulation is regarded as a pivotal step in the progression of heart failure which is associated with a high risk for arrhythmia. The cAMP-dependent transcription factors cAMP-responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) mediate transcriptional regulation in response to β-adrenergic stimulation and CREM repressor isoforms are induced after stimulation of the β-adrenoceptor. Here, we investigate whether CREM repressors contribute to the arrhythmogenic remodeling in the heart by analyzing arrhythmogenic alterations in ventricular cardiomyocytes (VCMs) from mice with transgenic expression of the CREM repressor isoform CREM-IbΔC-X (TG). Patch clamp analyses, calcium imaging, immunoblotting and real-time quantitative RT-PCR were conducted to study proarrhythmic alterations in TG VCMs vs. wild-type controls. The percentage of VCMs displaying spontaneous supra-threshold transient-like Ca2+ releases was increased in TG accompanied by an enhanced transduction rate of sub-threshold Ca2+ waves into these supra-threshold events. As a likely cause we discovered enhanced NCX-mediated Ca2+ transport and NCX1 protein level in TG. An increase in I _NCX and decrease in I _to and its accessory channel subunit KChIP2 was associated with action potential prolongation and an increased proportion of TG VCMs showing early afterdepolarizations. Finally, ventricular extrasystoles were augmented in TG mice underlining the in vivo relevance of our findings. Transgenic expression of CREM-IbΔC-X in mouse VCMs leads to distinct arrhythmogenic alterations. Since CREM repressors are inducible by chronic β-adrenergic stimulation our results suggest that the inhibition of CRE-dependent transcription contributes to the formation of an arrhythmogenic substrate in chronic heart disease. Keywords Transcription factor CREM Arrhythmia Remodeling NCX