Heart Failure Reviews

, Volume 21, Issue 6, pp 783–794 | Cite as

Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease

  • Alexander T. Mikhailov
  • Mario Torrado


There are multiple intrinsic mechanisms for diastolic dysfunction ranging from molecular to structural derangements in ventricular myocardium. The molecular mechanisms regulating the progression from normal diastolic function to severe dysfunction still remain poorly understood. Recent studies suggest a potentially important role of core cardio-enriched transcription factors (TFs) in the control of cardiac diastolic function in health and disease through their ability to regulate the expression of target genes involved in the process of adaptive and maladaptive cardiac remodeling. The current relevant findings on the role of a variety of such TFs (TBX5, GATA-4/6, SRF, MYOCD, NRF2, and PITX2) in cardiac diastolic dysfunction and failure are updated, emphasizing their potential as promising targets for novel treatment strategies. In turn, the new animal models described here will be key tools in determining the underlying molecular mechanisms of disease. Since diastolic dysfunction is regulated by various TFs, which are also involved in cross talk with each other, there is a need for more in-depth research from a biomedical perspective in order to establish efficient therapeutic strategies.


Diastolic dysfunction Transcription factors MicroRNAs 



This work was supported in part by funds from the Institute of Health Sciences and by a grant (GRC 2013/061) from the Autonomic Government of Galicia, Spain.

Compliance with ethical standards

The manuscript does not contain clinical studies or patient data.

Conflict of interest

The authors have declared that no competing interests exist.


  1. 1.
    Loffredo FS, Nikolova AP, Pancoast JR, Lee RT (2014) Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res 115:97–107. doi: 10.1161/CIRCRESAHA.115.302929 PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Sharma K, Kass DA (2014) Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 115:79–96. doi: 10.1161/CIRCRESAHA.115.302922 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Senni M, Paulus WJ, Gavazzi A, Fraser AG, Diez J, Solomon SD, Smiseth OA, Guazzi M, Lam CS, Maggioni AP et al (2014) New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 35:2797–2815. doi: 10.1093/eurheartj/ehu204 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Abbate A, Arena R, Abouzaki N, Van Tassell BW, Canada J, Shah K, Biondi-Zoccai G, Voelkel NF (2015) Heart failure with preserved ejection fraction: refocusing on diastole. Int J Cardiol 179:430–440. doi: 10.1016/j.ijcard.2014.11.106 PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrari R, Bohm M, Cleland JG, Paulus WJ, Pieske B, Rapezzi C, Tavazzi L (2015) Heart failure with preserved ejection fraction: uncertainties and dilemmas. Eur J Heart Fail 17:665–671. doi: 10.1002/ejhf.304 PubMedCrossRefGoogle Scholar
  6. 6.
    Oktay AA, Shah SJ (2015) Diagnosis and management of heart failure with preserved ejection fraction: 10 key lessons. Curr Cardiol Rev 11:42–52. doi: 10.2174/1573403X09666131117131217 PubMedCrossRefGoogle Scholar
  7. 7.
    Rodrigues PG, Leite-Moreira AF, Falcao-Pires I (2016) Myocardial reverse remodeling: how far can we rewind? Am J Physiol Heart Circ Physiol. doi: 10.1152/ajpheart.00696.2015 Google Scholar
  8. 8.
    Gomes AC, Falcao-Pires I, Pires AL, Bras-Silva C, Leite-Moreira AF (2013) Rodent models of heart failure: an updated review. Heart Fail Rev 18:219–249. doi: 10.1007/s10741-012-9305-3 PubMedCrossRefGoogle Scholar
  9. 9.
    Horgan S, Watson C, Glezeva N, Baugh J (2014) Murine models of diastolic dysfunction and heart failure with preserved ejection fraction. J Card Fail 20:984–995. doi: 10.1016/j.cardfail.2014.09.001 PubMedCrossRefGoogle Scholar
  10. 10.
    Connelly KA, Kelly DJ, Zhang Y, Prior DL, Martin J, Cox AJ, Thai K, Feneley MP, Tsoporis J, White KE et al (2007) Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat. Cardiovasc Res 76:280–291. doi: 10.1016/j.cardiores.2007.06.022 PubMedCrossRefGoogle Scholar
  11. 11.
    Hamdani N, Bishu KG, von Frieling-Salewsky M, Redfield MM, Linke WA (2013) Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction. Cardiovasc Res 97:464–471. doi: 10.1093/cvr/cvs353 PubMedCrossRefGoogle Scholar
  12. 12.
    Tong CW, Nair NA, Doersch KM, Liu Y, Rosas PC (2014) Cardiac myosin-binding protein-C is a critical mediator of diastolic function. Pflugers Arch 466:451–457. doi: 10.1007/s00424-014-1442-1 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Sheng JJ, Feng HZ, Pinto JR, Wei H, Jin JP (2015) Increases of desmin and alpha-actinin in mouse cardiac myofibrils as a response to diastolic dysfunction. J Mol Cell Cardiol. doi: 10.1016/j.yjmcc.2015.1010.1035 Google Scholar
  14. 14.
    Rysa J, Leskinen H, Ilves M, Ruskoaho H (2005) Distinct upregulation of extracellular matrix genes in transition from hypertrophy to hypertensive heart failure. Hypertension 45:927–933. doi: 10.1161/01.HYP.0000161873.27088.4c PubMedCrossRefGoogle Scholar
  15. 15.
    Phrommintikul A, Tran L, Kompa A, Wang B, Adrahtas A, Cantwell D, Kelly DJ, Krum H (2008) Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction. Am J Physiol Heart Circ Physiol 294:H1804–H1814. doi: 10.1152/ajpheart.01078.2007 PubMedCrossRefGoogle Scholar
  16. 16.
    Regan JA, Mauro AG, Carbone S, Marchetti C, Gill R, Mezzaroma E, Valle Raleigh J, Salloum FN, Van Tassell BW, Abbate A et al (2015) A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II. Am J Physiol Heart Circ Physiol 309:H771–H778. doi: 10.1152/ajpheart.00282.2015 PubMedPubMedCentralGoogle Scholar
  17. 17.
    Franssen C, Gonzalez Miqueo A (2016) The role of titin and extracellular matrix remodelling in heart failure with preserved ejection fraction. Neth Heart J 24:259–267. doi: 10.1007/s12471-016-0812-z PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Ingle KA, Kain V, Goel M, Prabhu SD, Young ME, Halade GV (2015) Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. Am J Physiol Heart Circ Physiol 309:H1827–H1836. doi: 10.1152/ajpheart.00608.2015 PubMedCrossRefGoogle Scholar
  19. 19.
    Jia G, Habibi J, DeMarco VG, Martinez-Lemus LA, Ma L, Whaley-Connell AT, Aroor AR, Domeier TL, Zhu Y, Meininger GA et al (2015) Endothelial mineralocorticoid receptor deletion prevents diet-induced cardiac diastolic dysfunction in females. Hypertension 66:1159–1167. doi: 10.1161/HYPERTENSIONAHA.115.06015 PubMedGoogle Scholar
  20. 20.
    Kathiriya IS, Nora EP, Bruneau BG (2015) Investigating the transcriptional control of cardiovascular development. Circ Res 116:700–714. doi: 10.1161/CIRCRESAHA.116.302832 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Nimura K, Kaneda Y (2015) Elucidating the mechanisms of transcription regulation during heart development by next-generation sequencing. J Hum Genet. doi: 10.1038/jhg.2015.1084 PubMedGoogle Scholar
  22. 22.
    Kohli S, Ahuja S, Rani V (2011) Transcription factors in heart: promising therapeutic targets in cardiac hypertrophy. Curr Cardiol Rev 7:262–271. doi: 10.2174/157340311799960618 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Mikhailov AT, Torrado M (2012) In search of novel targets for heart disease: myocardin and myocardin-related transcriptional cofactors. Biochem Res Int 2012:973723. doi: 10.1155/2012/973723 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Dirkx E, da Costa Martins PA, De Windt LJ (2013) Regulation of fetal gene expression in heart failure. Biochim Biophys Acta 1832:2414–2424. doi: 10.1016/j.bbadis.2013.07.023 PubMedCrossRefGoogle Scholar
  25. 25.
    Fontaine F, Overman J, Francois M (2015) Pharmacological manipulation of transcription factor protein-protein interactions: opportunities and obstacles. Cell Regen (Lond) 4:2. doi: 10.1186/s13619-015-0015-x CrossRefGoogle Scholar
  26. 26.
    Packham EA, Brook JD (2003) T-box genes in human disorders. Hum Mol Genet 12(Spec No 1):R37–R44. doi: 10.1093/hmg/ddg077
  27. 27.
    Plageman TF Jr, Yutzey KE (2005) T-box genes and heart development: putting the “T” in heart. Dev Dyn 232:11–20. doi: 10.1002/dvdy.20201 PubMedCrossRefGoogle Scholar
  28. 28.
    Papaioannou VE (2014) The T-box gene family: emerging roles in development, stem cells and cancer. Development 141:3819–3833. doi: 10.1242/dev.104471 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Hatcher CJ, Goldstein MM, Mah CS, Delia CS, Basson CT (2000) Identification and localization of TBX5 transcription factor during human cardiac morphogenesis. Dev Dyn 219:90–95. doi: 10.1002/1097-0177(200009)219:1<90:AID-DVDY1033>3.0.CO;2-L PubMedCrossRefGoogle Scholar
  30. 30.
    Mori AD, Zhu Y, Vahora I, Nieman B, Koshiba-Takeuchi K, Davidson L, Pizard A, Seidman JG, Seidman CE, Chen XJ et al (2006) Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis. Dev Biol 297:566–586. doi: 10.1016/j.ydbio.2006.05.023 PubMedCrossRefGoogle Scholar
  31. 31.
    Arnolds DE, Liu F, Fahrenbach JP, Kim GH, Schillinger KJ, Smemo S, McNally EM, Nobrega MA, Patel VV, Moskowitz IP (2012) TBX5 drives Scn5a expression to regulate cardiac conduction system function. J Clin Invest 122:2509–2518. doi: 10.1172/JCI62617 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Georges R, Nemer G, Morin M, Lefebvre C, Nemer M (2008) Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation. Mol Cell Biol 28:4052–4067. doi: 10.1128/MCB.02100-07 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Yamak A, Georges RO, Sheikh-Hassani M, Morin M, Komati H, Nemer M (2015) Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function. J Biol Chem 290:6844–6856. doi: 10.1074/jbc.M114.634451 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Liberatore CM, Searcy-Schrick RD, Yutzey KE (2000) Ventricular expression of tbx5 inhibits normal heart chamber development. Dev Biol 223:169–180. doi: 10.1006/dbio.2000.9748 PubMedCrossRefGoogle Scholar
  35. 35.
    Patel C, Silcock L, McMullan D, Brueton L, Cox H (2012) TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype. Eur J Hum Genet 20:863–869. doi: 10.1038/ejhg.2012.16 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Bruneau BG, Nemer G, Schmitt JP, Charron F, Robitaille L, Caron S, Conner DA, Gessler M, Nemer M, Seidman CE et al (2001) A murine model of Holt–Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106:709–721. doi: 10.1016/S0092-8674(01)00493-7 PubMedCrossRefGoogle Scholar
  37. 37.
    Al-Qattan MM, Abou Al-Shaar H (2015) Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications. Gene 560:129–136. doi: 10.1016/j.gene.2015.02.017 PubMedCrossRefGoogle Scholar
  38. 38.
    Zhu Y, Gramolini AO, Walsh MA, Zhou YQ, Slorach C, Friedberg MK, Takeuchi JK, Sun H, Henkelman RM, Backx PH et al (2008) Tbx5-dependent pathway regulating diastolic function in congenital heart disease. Proc Natl Acad Sci USA 105:5519–5524. doi: 10.1073/pnas.0801779105 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Antonini-Canterin F, Carerj S, Di Bello V, Di Salvo G, La Carrubba S, Vriz O, Pavan D, Balbarini A, Nicolosi GL (2009) Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist’s point of view. Eur J Echocardiogr 10:36–43. doi: 10.1093/ejechocard/jen236 PubMedCrossRefGoogle Scholar
  40. 40.
    Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T et al (2009) Genome-wide association study of blood pressure and hypertension. Nat Genet 41:677–687. doi: 10.1038/ng.384 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Zhou YQ, Zhu Y, Bishop J, Davidson L, Henkelman RM, Bruneau BG, Foster FS (2005) Abnormal cardiac inflow patterns during postnatal development in a mouse model of Holt–Oram syndrome. Am J Physiol Heart Circ Physiol 289:H992–H1001. doi: 10.1152/ajpheart.00027.2005 PubMedCrossRefGoogle Scholar
  42. 42.
    Pikkarainen S, Tokola H, Kerkela R, Ruskoaho H (2004) GATA transcription factors in the developing and adult heart. Cardiovasc Res 63:196–207. doi: 10.1016/j.cardiores.2004.03.025 PubMedCrossRefGoogle Scholar
  43. 43.
    Peterkin T, Gibson A, Loose M, Patient R (2005) The roles of GATA-4, -5 and -6 in vertebrate heart development. Semin Cell Dev Biol 16:83–94. doi: 10.1016/j.semcdb.2004.10.003 PubMedCrossRefGoogle Scholar
  44. 44.
    Rysa J, Tenhunen O, Serpi R, Soini Y, Nemer M, Leskinen H, Ruskoaho H (2010) GATA-4 is an angiogenic survival factor of the infarcted heart. Circ Heart Fail 3:440–450. doi: 10.1161/CIRCHEARTFAILURE.109.889642 PubMedCrossRefGoogle Scholar
  45. 45.
    Lepore JJ, Cappola TP, Mericko PA, Morrisey EE, Parmacek MS (2005) GATA-6 regulates genes promoting synthetic functions in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 25:309–314. doi: 10.1161/01.ATV.0000152725.76020.3c PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao R, Watt AJ, Battle MA, Li J, Bondow BJ, Duncan SA (2008) Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol 317:614–619. doi: 10.1016/j.ydbio.2008.03.013 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Liang Q, De Windt LJ, Witt SA, Kimball TR, Markham BE, Molkentin JD (2001) The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J Biol Chem 276:30245–30253. doi: 10.1074/jbc.M102174200 PubMedCrossRefGoogle Scholar
  48. 48.
    van Berlo JH, Aronow BJ, Molkentin JD (2013) Parsing the roles of the transcription factors GATA-4 and GATA-6 in the adult cardiac hypertrophic response. PLoS ONE 8:e84591. doi: 10.1371/journal.pone.0084591 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    van Berlo JH, Elrod JW, van den Hoogenhof MM, York AJ, Aronow BJ, Duncan SA, Molkentin JD (2010) The transcription factor GATA-6 regulates pathological cardiac hypertrophy. Circ Res 107:1032–1040. doi: 10.1161/CIRCRESAHA.110.220764 PubMedCrossRefGoogle Scholar
  50. 50.
    Oka T, Maillet M, Watt AJ, Schwartz RJ, Aronow BJ, Duncan SA, Molkentin JD (2006) Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ Res 98:837–845. doi: 10.1161/01.RES.0000215985.18538.c4 PubMedCrossRefGoogle Scholar
  51. 51.
    Prendiville TW, Guo H, Lin Z, Zhou P, Stevens SM, He A, VanDusen N, Chen J, Zhong L, Wang DZ et al (2015) Novel roles of GATA4/6 in the postnatal heart identified through temporally controlled, cardiomyocyte-specific gene inactivation by adeno-associated virus delivery of Cre recombinase. PLoS ONE 10:e0128105. doi: 10.1371/journal.pone.0128105 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Ishiwata T, Nakazawa M, Pu WT, Tevosian SG, Izumo S (2003) Developmental changes in ventricular diastolic function correlate with changes in ventricular myoarchitecture in normal mouse embryos. Circ Res 93:857–865. doi: 10.1161/01.RES.0000100389.57520.1A PubMedCrossRefGoogle Scholar
  53. 53.
    Pu WT, Ishiwata T, Juraszek AL, Ma Q, Izumo S (2004) GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Dev Biol 275:235–244. doi: 10.1016/j.ydbio.2004.08.008 PubMedCrossRefGoogle Scholar
  54. 54.
    Charron F, Paradis P, Bronchain O, Nemer G, Nemer M (1999) Cooperative interaction between GATA-4 and GATA-6 regulates myocardial gene expression. Mol Cell Biol 19:4355–4365PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    McCulley DJ, Black BL (2012) Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 100:253–277. doi: 10.1016/B978-0-12-387786-4.00008-7 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Zhou B, Ma Q, Kong SW, Hu Y, Campbell PH, McGowan FX, Ackerman KG, Wu B, Tevosian SG, Pu WT (2009) Fog2 is critical for cardiac function and maintenance of coronary vasculature in the adult mouse heart. J Clin Invest 119:1462–1476. doi: 10.1172/JCI38723 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Rouf R, Greytak S, Wooten EC, Wu J, Boltax J, Picard M, Svensson EC, Dillmann WH, Patten RD, Huggins GS (2008) Increased FOG-2 in failing myocardium disrupts thyroid hormone-dependent SERCA2 gene transcription. Circ Res 103:493–501. doi: 10.1161/CIRCRESAHA.108.181487 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Miano JM (2003) Serum response factor: toggling between disparate programs of gene expression. J Mol Cell Cardiol 35:577–593. doi: 10.1016/S0022-2828(03)00110-X PubMedCrossRefGoogle Scholar
  59. 59.
    Miano JM, Long X, Fujiwara K (2007) Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus. Am J Physiol Cell Physiol 292:C70–C81. doi: 10.1152/ajpcell.00386.2006 PubMedCrossRefGoogle Scholar
  60. 60.
    Zhang X, Azhar G, Helms S, Burton B, Huang C, Zhong Y, Gu X, Fang H, Tong W, Wei JY (2011) Identification of new SRF binding sites in genes modulated by SRF over-expression in mouse hearts. Gene Regul Syst Biol 5:41–59. doi: 10.4137/GRSB.S7457 Google Scholar
  61. 61.
    Miano JM (2010) Role of serum response factor in the pathogenesis of disease. Lab Invest 90:1274–1284. doi: 10.1038/labinvest.2010.104 PubMedCrossRefGoogle Scholar
  62. 62.
    Mikhailov AT, Torrado M (2010) NKX2.5 and SRF in postnatal cardiac remodeling: is there a link? In: Mikhailov AT, Torrado M (eds) Shaping the heart in development and disease. Transworld Research Network, Trivandrum, pp 145–164Google Scholar
  63. 63.
    Zhang X, Azhar G, Furr MC, Zhong Y, Wei JY (2003) Model of functional cardiac aging: young adult mice with mild overexpression of serum response factor. Am J Physiol Regul Integr Comp Physiol 285:R552–R560. doi: 10.1152/ajpregu.00631.2002 PubMedCrossRefGoogle Scholar
  64. 64.
    Angelini A, Li Z, Mericskay M, Decaux JF (2015) Regulation of connective tissue growth factor and cardiac fibrosis by an SRF/microRNA-133a Axis. PLoS ONE 10:e0139858. doi: 10.1371/journal.pone.0139858 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Cen B, Selvaraj A, Prywes R (2004) Myocardin/MKL family of SRF coactivators: key regulators of immediate early and muscle specific gene expression. J Cell Biochem 93:74–82. doi: 10.1002/jcb.20199 PubMedCrossRefGoogle Scholar
  66. 66.
    Pipes GC, Creemers EE, Olson EN (2006) The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev 20:1545–1556. doi: 10.1101/gad.1428006 PubMedCrossRefGoogle Scholar
  67. 67.
    Parmacek MS (2007) Myocardin-related transcription factors: critical coactivators regulating cardiovascular development and adaptation. Circ Res 100:633–644. doi: 10.1161/01.RES.0000259563.61091.e8 PubMedCrossRefGoogle Scholar
  68. 68.
    Miano JM (2015) Myocardin in biology and disease. J Biomed Res 29:3–19. doi: 10.7555/JBR.29.20140151 PubMedGoogle Scholar
  69. 69.
    Huang J, Min L, Cheng L, Yuan LJ, Zhu X, Stout AL, Chen M, Li J, Parmacek MS (2009) Myocardin is required for cardiomyocyte survival and maintenance of heart function. Proc Natl Acad Sci USA 106:18734–18739. doi: 10.1073/pnas.0910749106 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Torrado M, Centeno C, López E, Mikhailov AT (2009) In-vivo forced expression of myocardin in ventricular myocardium transiently impairs systolic performance in early neonatal pig heart. Int J Dev Biol 53:1457–1467. doi: 10.1387/ijdb.072366mt PubMedCrossRefGoogle Scholar
  71. 71.
    Kumar A, Crawford K, Close L, Madison M, Lorenz J, Doetschman T, Pawlowski S, Duffy J, Neumann J, Robbins J et al (1997) Rescue of cardiac alpha-actin-deficient mice by enteric smooth muscle gamma-actin. Proc Natl Acad Sci USA 94:4406–4411PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Torrado M, Iglesias R, Centeno A, Lopez E, Mikhailov AT (2011) Targeted gene-silencing reveals the functional significance of myocardin signaling in the failing heart. PLoS ONE 6:e26392. doi: 10.1371/journal.pone.0026392 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, Xue P, Pi J, Kleeberger SR, Bell DA (2012) Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res 40:7416–7429. doi: 10.1093/nar/gks409 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Jaiswal AK (2004) Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 36:1199–1207. doi: 10.1016/j.freeradbiomed.2004.02.074 PubMedCrossRefGoogle Scholar
  75. 75.
    Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol 244:37–42. doi: 10.1016/j.taap.2009.06.009 PubMedCrossRefGoogle Scholar
  76. 76.
    Li J, Ichikawa T, Janicki JS, Cui T (2009) Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets 13:785–794. doi: 10.1517/14728220903025762 PubMedCrossRefGoogle Scholar
  77. 77.
    Zhou S, Sun W, Zhang Z, Zheng Y (2014) The role of Nrf2-mediated pathway in cardiac remodeling and heart failure. Oxid Med Cell Longev 2014:260429. doi: 10.1155/2014/260429 PubMedPubMedCentralGoogle Scholar
  78. 78.
    Cho HY, Marzec J, Kleeberger SR (2015) Functional polymorphisms in Nrf2: implications for human disease. Free Radic Biol Med 88:362–372. doi: 10.1016/j.freeradbiomed.2015.06.012 PubMedCrossRefGoogle Scholar
  79. 79.
    Chan K, Lu R, Chang JC, Kan YW (1996) NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci USA 93:13943–13948PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Li J, Ichikawa T, Villacorta L, Janicki JS, Brower GL, Yamamoto M, Cui T (2009) Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol 29:1843–1850. doi: 10.1161/ATVBAHA.109.189480 PubMedCrossRefGoogle Scholar
  81. 81.
    Xu B, Zhang J, Strom J, Lee S, Chen QM (2014) Myocardial ischemic reperfusion induces de novo Nrf2 protein translation. Biochim Biophys Acta 1842:1638–1647. doi: 10.1016/j.bbadis.2014.06.002 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Tao G, Kahr PC, Morikawa Y, Zhang M, Rahmani M, Heallen TR, Li L, Sun Z, Olson EN, Amendt BA et al (2016) Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature. doi: 10.1038/nature17959 Google Scholar
  83. 83.
    Erkens R, Kramer CM, Luckstadt W, Panknin C, Krause L, Weidenbach M, Dirzka J, Krenz T, Mergia E, Suvorava T et al (2015) Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med 89:906–917. doi: 10.1016/j.freeradbiomed.2015.10.409 PubMedCrossRefGoogle Scholar
  84. 84.
    Howden R (2013) Nrf2 and cardiovascular defense. Oxid Med Cell Longev 2013:104308. doi: 10.1155/2013/104308 PubMedPubMedCentralGoogle Scholar
  85. 85.
    Cominacini L, Mozzini C, Garbin U, Pasini A, Stranieri C, Solani E, Vallerio P, Tinelli IA, Fratta Pasini A (2015) Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. Free Radic Biol Med 88:233–242. doi: 10.1016/j.freeradbiomed.2015.05.027 PubMedCrossRefGoogle Scholar
  86. 86.
    Seymour EM, Bennink MR, Bolling SF (2013) Diet-relevant phytochemical intake affects the cardiac AhR and nrf2 transcriptome and reduces heart failure in hypertensive rats. J Nutr Biochem 24:1580–1586. doi: 10.1016/j.jnutbio.2013.01.008 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    From AM, Scott CG, Chen HH (2010) The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol 55:300–305. doi: 10.1016/j.jacc.2009.12.003 PubMedCrossRefGoogle Scholar
  88. 88.
    Liu Q, Wang S, Cai L (2014) Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage. J Diabetes Investig 5:623–634. doi: 10.1111/jdi.12250 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Chen J, Zhang Z, Cai L (2014) Diabetic cardiomyopathy and its prevention by nrf2: current status. Diabetes Metab J 38:337–345. doi: 10.4093/dmj.2014.38.5.337 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, Siegel-Bartelt J, Bierke-Nelson D, Bitoun P, Zabel BU et al (1996) Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392–399. doi: 10.1038/ng1296-392 PubMedCrossRefGoogle Scholar
  91. 91.
    Hjalt TA, Semina EV (2005) Current molecular understanding of Axenfeld–Rieger syndrome. Expert Rev Mol Med 7:1–17. doi: 10.1017/S1462399405010082 PubMedCrossRefGoogle Scholar
  92. 92.
    Zhao CM, Peng LY, Li L, Liu XY, Wang J, Zhang XL, Yuan F, Li RG, Qiu XB, Yang YQ (2015) PITX2 loss-of-function mutation contributes to congenital endocardial cushion defect and Axenfeld–Rieger syndrome. PLoS ONE 10:e0124409. doi: 10.1371/journal.pone.0124409 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hjalt TA, Semina EV, Amendt BA, Murray JC (2000) The Pitx2 protein in mouse development. Dev Dyn 218:195–200. doi: 10.1002/(SICI)1097-0177(200005)218:1<195:AID-DVDY17>3.0.CO;2-C PubMedCrossRefGoogle Scholar
  94. 94.
    Kirchhof P, Kahr PC, Kaese S, Piccini I, Vokshi I, Scheld HH, Rotering H, Fortmueller L, Laakmann S, Verheule S et al (2011) PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet 4:123–133. doi: 10.1161/CIRCGENETICS.110.958058 PubMedCrossRefGoogle Scholar
  95. 95.
    Kahr PC, Piccini I, Fabritz L, Greber B, Scholer H, Scheld HH, Hoffmeier A, Brown NA, Kirchhof P (2011) Systematic analysis of gene expression differences between left and right atria in different mouse strains and in human atrial tissue. PLoS ONE 6:e26389. doi: 10.1371/journal.pone.0026389 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Hsu J, Hanna P, Van Wagoner DR, Barnard J, Serre D, Chung MK, Smith JD (2012) Whole genome expression differences in human left and right atria ascertained by RNA sequencing. Circ Cardiovasc Genet 5:327–335. doi: 10.1161/CIRCGENETICS.111.961631 PubMedCrossRefGoogle Scholar
  97. 97.
    Torrado M, Franco D, Hernandez-Torres F, Crespo-Leiro MG, Iglesias-Gil C, Castro-Beiras A, Mikhailov AT (2014) Pitx2c is reactivated in the failing myocardium and stimulates myf5 expression in cultured cardiomyocytes. PLoS ONE 9:e90561. doi: 10.1371/journal.pone.0090561 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hernandez-Torres F, Franco D, Aranega AE, Navarro F (2015) Expression patterns and immunohistochemical localization of PITX2B transcription factor in the developing mouse heart. Int J Dev Biol 59:247–254. doi: 10.1387/ijdb.140224fh PubMedCrossRefGoogle Scholar
  99. 99.
    Cox CJ, Espinoza HM, McWilliams B, Chappell K, Morton L, Hjalt TA, Semina EV, Amendt BA (2002) Differential regulation of gene expression by PITX2 isoforms. J Biol Chem 277:25001–25010. doi: 10.1074/jbc.M201737200 PubMedCrossRefGoogle Scholar
  100. 100.
    Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T, Ohgi KA, Lin C, Gleiberman A, Wang J et al (2002) Identification of a Wnt/Dvl/beta-Catenin – > Pitx2 pathway mediating cell-type-specific proliferation during development. Cell 111:673–685. doi: 10.1016/S0092-8674(02)01084-X PubMedCrossRefGoogle Scholar
  101. 101.
    Venugopalan SR, Amen MA, Wang J, Wong L, Cavender AC, D’Souza RN, Akerlund M, Brody SL, Hjalt TA, Amendt BA (2008) Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis. Hum Mol Genet 17:3643–3654. doi: 10.1093/hmg/ddn258 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Vadlamudi U, Espinoza HM, Ganga M, Martin DM, Liu X, Engelhardt JF, Amendt BA (2005) PITX2, beta-catenin and LEF-1 interact to synergistically regulate the LEF-1 promoter. J Cell Sci 118:1129–1137. doi: 10.1242/jcs.01706 PubMedCrossRefGoogle Scholar
  103. 103.
    Ganga M, Espinoza HM, Cox CJ, Morton L, Hjalt TA, Lee Y, Amendt BA (2003) PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5. J Biol Chem 278:22437–22445. doi: 10.1074/jbc.M210163200 PubMedCrossRefGoogle Scholar
  104. 104.
    Toro R, Saadi I, Kuburas A, Nemer M, Russo AF (2004) Cell-specific activation of the atrial natriuretic factor promoter by PITX2 and MEF2A. J Biol Chem 279:52087–52094. doi: 10.1074/jbc.M404802200 PubMedCrossRefGoogle Scholar
  105. 105.
    Zacharias AL, Lewandoski M, Rudnicki MA, Gage PJ (2011) Pitx2 is an upstream activator of extraocular myogenesis and survival. Dev Biol 349:395–405. doi: 10.1016/j.ydbio.2010.10.028 PubMedCrossRefGoogle Scholar
  106. 106.
    Zhou M, Liao Y, Tu X (2015) The role of transcription factors in atrial fibrillation. J Thorac Dis 7:152–158. doi: 10.3978/j.issn.2072-1439.2015.01.21 PubMedPubMedCentralGoogle Scholar
  107. 107.
    Tessari A, Pietrobon M, Notte A, Cifelli G, Gage PJ, Schneider MD, Lembo G, Campione M (2008) Myocardial Pitx2 differentially regulates the left atrial identity and ventricular asymmetric remodeling programs. Circ Res 102:813–822. doi: 10.1161/CIRCRESAHA.107.163188 PubMedCrossRefGoogle Scholar
  108. 108.
    Tao Y, Zhang M, Li L, Bai Y, Zhou Y, Moon AM, Kaminski HJ, Martin JF (2014) Pitx2, an atrial fibrillation predisposition gene, directly regulates ion transport and intercalated disc genes. Circ Cardiovasc Genet 7:23–32. doi: 10.1161/CIRCGENETICS.113.000259 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Chinchilla A, Daimi H, Lozano-Velasco E, Dominguez JN, Caballero R, Delpon E, Tamargo J, Cinca J, Hove-Madsen L, Aranega AE et al (2011) PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circ Cardiovasc Genet 4:269–279. doi: 10.1161/CIRCGENETICS.110.958116 PubMedCrossRefGoogle Scholar
  110. 110.
    Franco D, Chinchilla A, Aranega AE (2012) Transgenic insights linking pitx2 and atrial arrhythmias. Front Physiol 3:206. doi: 10.3389/fphys.2012.00206 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Franco D, Chinchilla A, Daimi H, Dominguez JN, Aranega A (2011) Modulation of conductive elements by Pitx2 and their impact on atrial arrhythmogenesis. Cardiovasc Res 91:223–231. doi: 10.1093/cvr/cvr078 PubMedCrossRefGoogle Scholar
  112. 112.
    Franco D, Christoffels VM, Campione M (2014) Homeobox transcription factor Pitx2: the rise of an asymmetry gene in cardiogenesis and arrhythmogenesis. Trends Cardiovasc Med 24:23–31. doi: 10.1016/j.tcm.2013.06.001 PubMedCrossRefGoogle Scholar
  113. 113.
    Huang Y, Wang C, Yao Y, Zuo X, Chen S, Xu C, Zhang H, Lu Q, Chang L, Wang F et al (2015) Molecular basis of gene-gene interaction: cyclic cross-regulation of gene expression and post-GWAS gene–gene interaction involved in atrial fibrillation. PLoS Genet 11:e1005393. doi: 10.1371/journal.pgen.1005393 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Torrado M, Franco D, Lozano-Velasco E, Hernandez-Torres F, Calvino R, Aldama G, Centeno A, Castro-Beiras A, Mikhailov A (2015) A microRNA-transcription factor blueprint for early atrial arrhythmogenic remodeling. Biomed Res Int 2015:263151. doi: 10.1155/2015/263151 PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Santerre RF, Bales KR, Janney MJ, Hannon K, Fisher LF, Bailey CS, Morris J, Ivarie R, Smith CK 2nd (1993) Expression of bovine myf5 induces ectopic skeletal muscle formation in transgenic mice. Mol Cell Biol 13:6044–6051PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Edwards JG, Lyons GE, Micales BK, Malhotra A, Factor S, Leinwand LA (1996) Cardiomyopathy in transgenic myf5 mice. Circ Res 78:379–387. doi: 10.1161/01.RES.78.3.379 PubMedCrossRefGoogle Scholar
  117. 117.
    Sun N, Yazawa M, Liu J, Han L, Sanchez-Freire V, Abilez OJ, Navarrete EG, Hu S, Wang L, Lee A et al (2012) Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med 4:130ra147. doi: 10.1126/scitranslmed.3003552 CrossRefGoogle Scholar
  118. 118.
    Su D, Jing S, Guan L, Li Q, Zhang H, Gao X, Ma X (2014) Role of Nodal-PITX2C signaling pathway in glucose-induced cardiomyocyte hypertrophy. Biochem Cell Biol 92:183–190. doi: 10.1139/bcb-2013-0124 PubMedCrossRefGoogle Scholar
  119. 119.
    Scimia MC, Sydnes KE, Zuppo DA, Koch WJ (2014) Methods to improve cardiac gene therapy expression. Expert Rev Cardiovasc Ther 12:1317–1326. doi: 10.1586/14779072.2014.967683 PubMedCrossRefGoogle Scholar
  120. 120.
    Nair N, Gupta S, Collier IX, Gongora E, Vijayaraghavan K (2014) Can microRNAs emerge as biomarkers in distinguishing HFpEF versus HFrEF? Int J Cardiol 175:395–399. doi: 10.1016/j.ijcard.2014.06.027 PubMedCrossRefGoogle Scholar
  121. 121.
    Wang F, Yang XY, Zhao JY, Yu LW, Zhang P, Duan WY, Chong M, Gui YH (2014) miR-10a and miR-10b target the 3′-untranslated region of TBX5 to repress its expression. Pediatr Cardiol 35:1072–1079. doi: 10.1007/s00246-014-0901-y PubMedCrossRefGoogle Scholar
  122. 122.
    Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP, Chen JF, Deng Z, Gunn B, Shumate J et al (2009) MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest 119:2772–2786. doi: 10.1172/JCI36154 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Han M, Yang Z, Sayed D, He M, Gao S, Lin L, Yoon S, Abdellatif M (2012) GATA4 expression is primarily regulated via a miR-26b-dependent post-transcriptional mechanism during cardiac hypertrophy. Cardiovasc Res 93:645–654. doi: 10.1093/cvr/cvs001 PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, Bassel-Duby R, Olson EN (2008) MicroRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev 22:3242–3254. doi: 10.1101/gad.1738708 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Wang DZ (2010) MicroRNAs in cardiac development and remodeling. Pediatr Cardiol 31:357–362. doi: 10.1007/s00246-010-9641-9 PubMedCrossRefGoogle Scholar
  126. 126.
    Liao XH, Wang N, Zhao DW, Zheng DL, Zheng L, Xing WJ, Zhou H, Cao DS, Zhang TC (2014) NF-kappaB (p65) negatively regulates myocardin-induced cardiomyocyte hypertrophy through multiple mechanisms. Cell Signal 26:2738–2748. doi: 10.1016/j.cellsig.2014.08.006 PubMedCrossRefGoogle Scholar
  127. 127.
    Wang K, Long B, Zhou J, Li PF (2010) MiR-9 and NFATc3 regulate myocardin in cardiac hypertrophy. J Biol Chem 285:11903–11912. doi: 10.1074/jbc.M109.098004 PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Nair N, Kumar S, Gongora E, Gupta S (2013) Circulating miRNA as novel markers for diastolic dysfunction. Mol Cell Biochem 376:33–40. doi: 10.1007/s11010-012-1546-x PubMedCrossRefGoogle Scholar
  129. 129.
    Marchler-Bauer A, Derbyshire MK, Gonzales NR, Lu S, Chitsaz F, Geer LY, Geer RC, He J, Gwadz M, Hurwitz DI et al (2015) CDD: NCBI’s conserved domain database. Nucleic Acids Res 43:D222–D226. doi: 10.1093/nar/gku1221 PubMedCrossRefGoogle Scholar
  130. 130.
    Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K et al (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447. doi: 10.1038/nature01827 PubMedCrossRefGoogle Scholar
  131. 131.
    Kodo K, Nishizawa T, Furutani M, Arai S, Ishihara K, Oda M, Makino S, Fukuda K, Takahashi T, Matsuoka R et al (2012) Genetic analysis of essential cardiac transcription factors in 256 patients with non-syndromic congenital heart defects. Circ J 76:1703–1711. doi: 10.1253/circj.CJ-11-1389 PubMedCrossRefGoogle Scholar
  132. 132.
    Wang C, Cao D, Wang Q, Wang DZ (2011) Synergistic activation of cardiac genes by myocardin and Tbx5. PLoS ONE 6:e24242. doi: 10.1371/journal.pone.0024242 PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Shang Y, Yoshida T, Amendt BA, Martin JF, Owens GK (2008) Pitx2 is functionally important in the early stages of vascular smooth muscle cell differentiation. J Cell Biol 181:461–473. doi: 10.1083/jcb.200711145 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Martin DM, Amendt BA, Brown NA (2010) Pitx2 in cardiac left–right asymmetry and human disease. In: Rosenthal N, Harvey RP (eds) Heart development and regeneration, vol 1. Academic Press, New York, pp 307–320CrossRefGoogle Scholar
  135. 135.
    Diedrichs H, Chi M, Boelck B, Mehlhorn U, Schwinger RH (2004) Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure. Eur J Heart Fail 6:3–9. doi: 10.1016/j.ejheart.2003.07.007 PubMedCrossRefGoogle Scholar
  136. 136.
    Chang J, Wei L, Otani T, Youker KA, Entman ML, Schwartz RJ (2003) Inhibitory cardiac transcription factor, SRF-N, is generated by caspase 3 cleavage in human heart failure and attenuated by ventricular unloading. Circulation 108:407–413. doi: 10.1161/01.CIR.0000084502.02147.83 PubMedCrossRefGoogle Scholar
  137. 137.
    Torrado M, Lopez E, Centeno A, Medrano C, Castro-Beiras A, Mikhailov AT (2003) Myocardin mRNA is augmented in the failing myocardium: expression profiling in the porcine model and human dilated cardiomyopathy. J Mol Med 81:566–577PubMedCrossRefGoogle Scholar
  138. 138.
    Tan Y, Ichikawa T, Li J, Si Q, Yang H, Chen X, Goldblatt CS, Meyer CJ, Li X, Cai L et al (2011) Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes 60:625–633. doi: 10.2337/db10-1164 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Institute of Health SciencesUniversity of La CoruñaLa CoruñaSpain

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