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Molecular Targets in the Treatment of Cardiac Hypertrophy

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Pathophysiology and Pharmacotherapy of Cardiovascular Disease

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Abstract

Cardiac hypertrophy is associated with a variety of widespread disorders such as ischemic, valvular, and hypertensive heart disease. It has been identified as an independent risk factor for heart failure and mortality. Therefore, prevention as well as reversal of cardiac hypertrophy represents an obvious goal in the treatment of these patients. So far, established drug therapies target mainly α- and β-adrenergic receptors as well as the renin-angiotensin-aldosterone system. However, many other molecular pathways have been found to contribute in the pathogenesis of pathological hypertrophy. Hypertrophic signaling is controlled on transcriptional and posttranscriptional level. The recent discovery of several noncoding RNA species has added another layer of complexity to the regulation of posttranscriptional gene expression. Furthermore, posttranslational modifications such as phosphorylation influence the activity of hypertrophic signaling. Finally, protein degradation mechanisms affect hypertrophic pathways. With growing knowledge about the molecular regulation of cardiac hypertrophy, novel targets will arise for medical therapy. In this chapter, we will provide a brief overview over selected pathways and highlight the impact of general mechanisms on hypertrophic signaling.

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References

  1. Li F, Wang X, Capasso JM, Gerdes AM. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol. 1996;28(8):1737–46. doi:10.1006/jmcc.1996.0163.

    CAS  PubMed  Google Scholar 

  2. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med. 2008;358(13):1370–80. doi:10.1056/NEJMra072139.

    CAS  PubMed  Google Scholar 

  3. Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation. 2004;109(13):1580–9. doi:10.1161/01.CIR.0000120390.68287.BB.

    PubMed  Google Scholar 

  4. de Simone G, Gottdiener JS, Chinali M, Maurer MS. Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study. Eur Heart J. 2008;29(6):741–7. doi:10.1093/eurheartj/ehm605.

    PubMed  Google Scholar 

  5. Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol. 1987;60(7):560–5.

    CAS  PubMed  Google Scholar 

  6. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322(22):1561–6. doi:10.1056/NEJM199005313222203.

    CAS  PubMed  Google Scholar 

  7. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003;63(6):1256–72. doi:10.1124/mol.63.6.1256.

    CAS  PubMed  Google Scholar 

  8. Lohse MJ, Engelhardt S, Eschenhagen T. What is the role of beta-adrenergic signaling in heart failure? Circ Res. 2003;93(10):896–906. doi:10.1161/01.RES.0000102042.83024.CA.

    CAS  PubMed  Google Scholar 

  9. Rockman HA, Koch WJ, Lefkowitz RJ. Seven-transmembrane-spanning receptors and heart function. Nature. 2002;415(6868):206–12. doi:10.1038/415206a.

    CAS  PubMed  Google Scholar 

  10. Rohrer DK, Desai KH, Jasper JR, Stevens ME, Regula Jr DP, Barsh GS, Bernstein D, Kobilka BK. Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects. Proc Natl Acad Sci U S A. 1996;93(14):7375–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Engelhardt S, Hein L, Wiesmann F, Lohse MJ. Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A. 1999;96(12):7059–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Bisognano JD, Weinberger HD, Bohlmeyer TJ, Pende A, Raynolds MV, Sastravaha A, Roden R, Asano K, Blaxall BC, Wu SC, Communal C, Singh K, Colucci W, Bristow MR, Port DJ. Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice. J Mol Cell Cardiol. 2000;32(5):817–30. doi:10.1006/jmcc.2000.1123.

    CAS  PubMed  Google Scholar 

  13. Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science. 1994;264(5158):582–6.

    CAS  PubMed  Google Scholar 

  14. Du XJ, Autelitano DJ, Dilley RJ, Wang B, Dart AM, Woodcock EA. Beta(2)-adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis. Circulation. 2000;101(1):71–7.

    CAS  PubMed  Google Scholar 

  15. Du XJ, Gao XM, Jennings GL, Dart AM, Woodcock EA. Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)-adrenergic receptors. Am J Physiol Heart Circ Physiol. 2000;279(5):H2456–63.

    CAS  PubMed  Google Scholar 

  16. Liggett SB, Tepe NM, Lorenz JN, Canning AM, Jantz TD, Mitarai S, Yatani A, Dorn 2nd GW. Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation. 2000;101(14):1707–14.

    CAS  PubMed  Google Scholar 

  17. Chruscinski AJ, Rohrer DK, Schauble E, Desai KH, Bernstein D, Kobilka BK. Targeted disruption of the beta2 adrenergic receptor gene. J Biol Chem. 1999;274(24):16694–700.

    CAS  PubMed  Google Scholar 

  18. Revelli JP, Preitner F, Samec S, Muniesa P, Kuehne F, Boss O, Vassalli JD, Dulloo A, Seydoux J, Giacobino JP, Huarte J, Ody C. Targeted gene disruption reveals a leptin-independent role for the mouse beta3-adrenoceptor in the regulation of body composition. J Clin Invest. 1997;100(5):1098–106. doi:10.1172/JCI119620.

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Kohout TA, Takaoka H, McDonald PH, Perry SJ, Mao L, Lefkowitz RJ, Rockman HA. Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice. Circulation. 2001;104(20):2485–91.

    CAS  PubMed  Google Scholar 

  20. Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000;101(5):558–69.

    CAS  PubMed  Google Scholar 

  21. Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res. 2013;113(6):739–53. doi:10.1161/CIRCRESAHA.113.300308.

    CAS  PubMed  Google Scholar 

  22. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients. A metaanalysis of 109 treatment studies. Am J Hypertens. 1992;5(2):95–110.

    CAS  PubMed  Google Scholar 

  23. Bangalore S, Messerli FH, Kostis JB, Pepine CJ. Cardiovascular protection using beta-blockers: a critical review of the evidence. J Am Coll Cardiol. 2007;50(7):563–72. doi:10.1016/j.jacc.2007.04.060.

    CAS  PubMed  Google Scholar 

  24. Pitcher JA, Freedman NJ, Lefkowitz RJ. G protein-coupled receptor kinases. Annu Rev Biochem. 1998;67:653–92. doi:10.1146/annurev.biochem.67.1.653.

    CAS  PubMed  Google Scholar 

  25. Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation. 1993;87(2):454–63.

    CAS  PubMed  Google Scholar 

  26. Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross Jr J, Lefkowitz RJ, Caron MG, Giros B. Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci U S A. 1996;93(23):12974–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Matkovich SJ, Diwan A, Klanke JL, Hammer DJ, Marreez Y, Odley AM, Brunskill EW, Koch WJ, Schwartz RJ, Dorn 2nd GW. Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling. Circ Res. 2006;99(9):996–1003. doi:10.1161/01.RES.0000247932.71270.2c.

    CAS  PubMed  Google Scholar 

  28. Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X, DeGeorge Jr BR, Matkovich S, Houser SR, Most P, Eckhart AD, Dorn 2nd GW, Koch WJ. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res. 2008;103(4):413–22. doi:10.1161/CIRCRESAHA.107.168336.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Rockman HA, Chien KR, Choi DJ, Iaccarino G, Hunter JJ, Ross Jr J, Lefkowitz RJ, Koch WJ. Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A. 1998;95(12):7000–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, Iaccarino G, Koch WJ, Leinwand LA. Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J Clin Invest. 2001;107(8):967–74. doi:10.1172/JCI12083.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Raake PW, Schlegel P, Ksienzyk J, Reinkober J, Barthelmes J, Schinkel S, Pleger S, Mier W, Haberkorn U, Koch WJ, Katus HA, Most P, Muller OJ. AAV6.betaARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model. Eur Heart J. 2013;34(19):1437–47. doi:10.1093/eurheartj/ehr447.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Casey LM, Pistner AR, Belmonte SL, Migdalovich D, Stolpnik O, Nwakanma FE, Vorobiof G, Dunaevsky O, Matavel A, Lopes CM, Smrcka AV, Blaxall BC. Small molecule disruption of G beta gamma signaling inhibits the progression of heart failure. Circ Res. 2010;107(4):532–9. doi:10.1161/CIRCRESAHA.110.217075.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Dell’Italia LJ. Translational success stories: angiotensin receptor 1 antagonists in heart failure. Circ Res. 2011;109(4):437–52. doi:10.1161/CIRCRESAHA.110.238550.

    PubMed  Google Scholar 

  34. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H, Group LS. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311):995–1003. doi:10.1016/S0140-6736(02)08089-3.

    CAS  PubMed  Google Scholar 

  35. Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375(9722):1255–66. doi:10.1016/S0140-6736(09)61966-8.

    CAS  PubMed  Google Scholar 

  36. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, Investigators P-H, Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004. doi:10.1056/NEJMoa1409077.

    PubMed  Google Scholar 

  37. Potter LR. Natriuretic peptide metabolism, clearance and degradation. FEBS J. 2011;278(11):1808–17. doi:10.1111/j.1742-4658.2011.08082.x.

    CAS  PubMed  Google Scholar 

  38. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ, Prospective comparison of AwARBoMOhfwpefI. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387–95. doi:10.1016/S0140-6736(12)61227-6.

    CAS  PubMed  Google Scholar 

  39. Wilkins BJ, Molkentin JD. Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. Biochem Biophys Res Commun. 2004;322(4):1178–91.

    CAS  PubMed  Google Scholar 

  40. Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 2002;109(Suppl):S67–79.

    CAS  PubMed  Google Scholar 

  41. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998;93(2):215–28.

    CAS  PubMed  Google Scholar 

  42. Lim HW, Molkentin JD. Calcineurin and human heart failure. Nat Med. 1999;5(3):246–7. doi:10.1038/6430.

    CAS  PubMed  Google Scholar 

  43. Bueno OF, Wilkins BJ, Tymitz KM, Glascock BJ, Kimball TF, Lorenz JN, Molkentin JD. Impaired cardiac hypertrophic response in calcineurin A beta-deficient mice. Proc Natl Acad Sci U S A. 2002;99(7):4586–91. doi:10.1073/pnas.072647999.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Zhang BW, Zimmer G, Chen J, Ladd D, Li E, Alt FW, Wiederrecht G, Cryan J, O’Neill EA, Seidman CE, Abbas AK, Seidman JG. T cell responses in calcineurin A alpha-deficient mice. J Exp Med. 1996;183(2):413–20.

    CAS  PubMed  Google Scholar 

  45. Maillet M, Davis J, Auger-Messier M, York A, Osinska H, Piquereau J, Lorenz JN, Robbins J, Ventura-Clapier R, Molkentin JD. Heart-specific deletion of CnB1 reveals multiple mechanisms whereby calcineurin regulates cardiac growth and function. J Biol Chem. 2010;285(9):6716–24. doi:10.1074/jbc.M109.056143.

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Bourajjaj M, Armand AS, da Costa Martins PA, Weijts B, van der Nagel R, Heeneman S, Wehrens XH, De Windt LJ. NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure. J Biol Chem. 2008;283(32):22295–303. doi:10.1074/jbc.M801296200.

    CAS  PubMed  Google Scholar 

  47. Wilkins BJ, De Windt LJ, Bueno OF, Braz JC, Glascock BJ, Kimball TF, Molkentin JD. Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol Cell Biol. 2002;22(21):7603–13.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Heineke J, Ritter O. Cardiomyocyte calcineurin signaling in subcellular domains: from the sarcolemma to the nucleus and beyond. J Mol Cell Cardiol. 2012;52(1):62–73. doi:10.1016/j.yjmcc.2011.10.018.

    CAS  PubMed  Google Scholar 

  49. Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci U S A. 2000;97(26):14632–7. doi:10.1073/pnas.260501097.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Frey N, Olson EN. Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J Biol Chem. 2002;277(16):13998–4004. doi:10.1074/jbc.M200712200.

    CAS  PubMed  Google Scholar 

  51. Frey N, Barrientos T, Shelton JM, Frank D, Rutten H, Gehring D, Kuhn C, Lutz M, Rothermel B, Bassel-Duby R, Richardson JA, Katus HA, Hill JA, Olson EN. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nat Med. 2004;10(12):1336–43. doi:10.1038/nm1132.

    CAS  PubMed  Google Scholar 

  52. Frank D, Kuhn C, van Eickels M, Gehring D, Hanselmann C, Lippl S, Will R, Katus HA, Frey N. Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy. Circulation. 2007;116(22):2587–96. doi:10.1161/CIRCULATIONAHA.107.711317.

    CAS  PubMed  Google Scholar 

  53. Paulsson AK, Franklin S, Mitchell-Jordan SA, Ren S, Wang Y, Vondriska TM. Post-translational regulation of calsarcin-1 during pressure overload-induced cardiac hypertrophy. J Mol Cell Cardiol. 2010;48(6):1206–14. doi:10.1016/j.yjmcc.2010.02.009.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Burkard N, Becher J, Heindl C, Neyses L, Schuh K, Ritter O. Targeted proteolysis sustains calcineurin activation. Circulation. 2005;111(8):1045–53. doi:10.1161/01.CIR.0000156458.80515.F7.

    CAS  PubMed  Google Scholar 

  55. Heineke J, Ruetten H, Willenbockel C, Gross SC, Naguib M, Schaefer A, Kempf T, Hilfiker-Kleiner D, Caroni P, Kraft T, Kaiser RA, Molkentin JD, Drexler H, Wollert KC. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. Proc Natl Acad Sci U S A. 2005;102(5):1655–60. doi:10.1073/pnas.0405488102.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Arber S, Hunter JJ, Ross Jr J, Hongo M, Sansig G, Borg J, Perriard JC, Chien KR, Caroni P. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell. 1997;88(3):393–403. doi:10.1016/S0092-8674(00)81878-4.

    CAS  PubMed  Google Scholar 

  57. Kuhn C, Frank D, Dierck F, Oehl U, Krebs J, Will R, Lehmann LH, Backs J, Katus HA, Frey N. Cardiac remodeling is not modulated by overexpression of muscle LIM protein (MLP). Basic Res Cardiol. 2012;107(3):262. doi:10.1007/s00395-012-0262-8.

    PubMed  Google Scholar 

  58. Boateng SY, Belin RJ, Geenen DL, Margulies KB, Martin JL, Hoshijima M, de Tombe PP, Russell B. Cardiac dysfunction and heart failure are associated with abnormalities in the subcellular distribution and amounts of oligomeric muscle LIM protein. Am J Physiol Heart Circ Physiol. 2007;292(1):H259–69. doi:10.1152/ajpheart.00766.2006.

    CAS  PubMed  Google Scholar 

  59. Jeong D, Kim JM, Cha H, Oh JG, Park J, Yun SH, Ju ES, Jeon ES, Hajjar RJ, Park WJ. PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling. Circ Res. 2008;102(6):711–9. doi:10.1161/CIRCRESAHA.107.165985.

    CAS  PubMed  Google Scholar 

  60. Frank D, Frauen R, Hanselmann C, Kuhn C, Will R, Gantenberg J, Fuzesi L, Katus HA, Frey N. Lmcd1/Dyxin, a novel Z-disc associated LIM protein, mediates cardiac hypertrophy in vitro and in vivo. J Mol Cell Cardiol. 2010;49(4):673–82. doi:10.1016/j.yjmcc.2010.06.009.

    CAS  PubMed  Google Scholar 

  61. Heineke J, Auger-Messier M, Correll RN, Xu J, Benard MJ, Yuan W, Drexler H, Parise LV, Molkentin JD. CIB1 is a regulator of pathological cardiac hypertrophy. Nat Med. 2010;16(8):872–9. doi:10.1038/nm.2181.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Taigen T, De Windt LJ, Lim HW, Molkentin JD. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2000;97(3):1196–201.

    PubMed Central  CAS  PubMed  Google Scholar 

  63. De Windt LJ, Lim HW, Bueno OF, Liang Q, Delling U, Braz JC, Glascock BJ, Kimball TF, del Monte F, Hajjar RJ, Molkentin JD. Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2001;98(6):3322–7. doi:10.1073/pnas.031371998.

    PubMed Central  PubMed  Google Scholar 

  64. Rothermel B, Vega RB, Yang J, Wu H, Bassel-Duby R, Williams RS. A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J Biol Chem. 2000;275:8719.

    CAS  PubMed  Google Scholar 

  65. Hill JA, Rothermel B, Yoo KD, Cabuay B, Demetroulis E, Weiss RM, Kutschke W, Bassel-Duby R, Williams RS. Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. J Biol Chem. 2002;277(12):10251–5. doi:10.1074/jbc.M110722200.

    CAS  PubMed  Google Scholar 

  66. Rothermel BA, McKinsey TA, Vega RB, Nicol RL, Mammen P, Yang J, Antos CL, Shelton JM, Bassel-Duby R, Olson EN, Williams RS. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2001;98(6):3328–33. doi:10.1073/pnas.041614798.

    PubMed Central  CAS  PubMed  Google Scholar 

  67. Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, Carinci P, Min KT, Fox DS, Cunningham KW, Bassel-Duby R, Olson EN, Zhang Z, Williams RS, Gerber HP, Perez-Riba M, Seo H, Cao X, Klee CB, Redondo JM, Maltais LJ, Bruford EA, Povey S, Molkentin JD, McKeon FD, Duh EJ, Crabtree GR, Cyert MS, de la Luna S, Estivill X. Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J. 2007;21(12):3023–8. doi:10.1096/fj.06-7246com.

    CAS  PubMed  Google Scholar 

  68. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res. 2000;87(12):E61–8.

    CAS  PubMed  Google Scholar 

  69. Vega RB, Rothermel BA, Weinheimer CJ, Kovacs A, Naseem RH, Bassel-Duby R, Williams RS, Olson EN. Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy. Proc Natl Acad Sci U S A. 2003;100(2):669–74. doi:10.1073/pnas.0237225100.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Sanna B, Brandt EB, Kaiser RA, Pfluger P, Witt SA, Kimball TR, van Rooij E, De Windt LJ, Rothenberg ME, Tschop MH, Benoit SC, Molkentin JD. Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitators in vivo. Proc Natl Acad Sci U S A. 2006;103(19):7327–32. doi:10.1073/pnas.0509340103.

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Hilioti Z, Gallagher DA, Low-Nam ST, Ramaswamy P, Gajer P, Kingsbury TJ, Birchwood CJ, Levchenko A, Cunningham KW. GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Genes Dev. 2004;18(1):35–47. doi:10.1101/gad.1159204.

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Jung MS, Park JH, Ryu YS, Choi SH, Yoon SH, Kwen MY, Oh JY, Song WJ, Chung SH. Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation. J Biol Chem. 2011;286(46):40401–12. doi:10.1074/jbc.M111.253971.

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, Joost HG. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem. 1998;273(40):25893–902.

    CAS  PubMed  Google Scholar 

  74. Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature. 2006;441(7093):646–50.

    CAS  PubMed  Google Scholar 

  75. Kuhn C, Frank D, Will R, Jaschinski C, Frauen R, Katus HA, Frey N. DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy. J Biol Chem. 2009;284(25):17320–7. doi:10.1074/jbc.M109.006759. M109.006759 [pii].

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Fotaki V, Dierssen M, Alcantara S, Martinez S, Marti E, Casas C, Visa J, Soriano E, Estivill X, Arbones ML. Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol Cell Biol. 2002;22(18):6636–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  77. da Costa Martins PA, Salic K, Gladka MM, Armand AS, Leptidis S, el Azzouzi H, Hansen A, Coenen-de Roo CJ, Bierhuizen MF, van der Nagel R, van Kuik J, de Weger R, de Bruin A, Condorelli G, Arbones ML, Eschenhagen T, De Windt LJ. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nat Cell Biol. 2010;12(12):1220–7. doi:10.1038/ncb2126.

    PubMed  Google Scholar 

  78. Grebe C, Klingebiel TM, Grau SP, Toischer K, Didie M, Jacobshagen C, Dullin C, Hasenfuss G, Seidler T. Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo. Cardiovasc Res. 2011;90(3):521–8. doi:10.1093/cvr/cvr023.

    CAS  PubMed  Google Scholar 

  79. Sugden PH, Fuller SJ, Weiss SC, Clerk A. Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis. Br J Pharmacol. 2008;153 Suppl 1:S137–53.

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Haq S, Choukroun G, Kang ZB, Ranu H, Matsui T, Rosenzweig A, Molkentin JD, Alessandrini A, Woodgett J, Hajjar R, Michael A, Force T. Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy. J Cell Biol. 2000;151(1):117–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN. Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2002;99(2):907–12. doi:10.1073/pnas.231619298.

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Yang XJ, Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol. 2008;9(3):206–18. doi:10.1038/nrm2346.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Gershey EL, Vidali G, Allfrey VG. Chemical studies of histone acetylation. The occurrence of epsilon-N-acetyllysine in the f2a1 histone. J Biol Chem. 1968;243(19):5018–22.

    CAS  PubMed  Google Scholar 

  84. Pazin MJ, Kadonaga JT. What’s up and down with histone deacetylation and transcription? Cell. 1997;89(3):325–8.

    CAS  PubMed  Google Scholar 

  85. Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem. 2007;76:75–100. doi:10.1146/annurev.biochem.76.052705.162114.

    CAS  PubMed  Google Scholar 

  86. Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene. 2005;363:15–23. doi:10.1016/j.gene.2005.09.010.

    CAS  PubMed  Google Scholar 

  87. Gregoretti IV, Lee YM, Goodson HV. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol. 2004;338(1):17–31. doi:10.1016/j.jmb.2004.02.006.

    CAS  PubMed  Google Scholar 

  88. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1(4):287–99. doi:10.1038/nrd772.

    CAS  PubMed  Google Scholar 

  89. Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol. 2007;25(1):84–90. doi:10.1038/nbt1272.

    CAS  PubMed  Google Scholar 

  90. Lu J, McKinsey TA, Nicol RL, Olson EN. Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci U S A. 2000;97(8):4070–5. doi:10.1073/pnas.080064097.

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, Kouzarides T. HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J. 1999;18(18):5099–107. doi:10.1093/emboj/18.18.5099.

    PubMed Central  CAS  PubMed  Google Scholar 

  92. Passier R, Zeng H, Frey N, Naya FJ, Nicol RL, McKinsey TA, Overbeek P, Richardson JA, Grant SR, Olson EN. CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest. 2000;105(10):1395–406. doi:10.1172/JCI8551.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest. 2006;116(7):1853–64. doi:10.1172/JCI27438.

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, McKinsey TA. Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Mol Cell Biol. 2004;24(19):8374–85. doi:10.1128/MCB. 24.19.8374-8385.2004.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002;110(4):479–88.

    CAS  PubMed  Google Scholar 

  96. Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol. 2004;24(19):8467–76. doi:10.1128/MCB. 24.19.8467-8476.2004.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF, Sadoshima J. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res. 2007;100(10):1512–21. doi:10.1161/01.RES.0000267723.65696.4a.

    CAS  PubMed  Google Scholar 

  98. Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J. Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res. 2004;95(10):971–80. doi:10.1161/01.RES.0000147557.75257.ff.

    CAS  PubMed  Google Scholar 

  99. Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Braun T, Bober E. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res. 2008;102(6):703–10. doi:10.1161/CIRCRESAHA.107.164558.

    CAS  PubMed  Google Scholar 

  100. Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 2007;21(14):1790–802. doi:10.1101/gad.1563807.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, Ferrari VA, Abrams CS, Gruber PJ, Epstein JA. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med. 2007;13(3):324–31. doi:10.1038/nm1552.

    CAS  PubMed  Google Scholar 

  102. Trivedi CM, Lu MM, Wang Q, Epstein JA. Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy. J Biol Chem. 2008;283(39):26484–9. doi:10.1074/jbc.M803686200.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R. Chemical phylogenetics of histone deacetylases. Nat Chem Biol. 2010;6(3):238–43. doi:10.1038/nchembio.313.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Kook H, Lepore JJ, Gitler AD, Lu MM, Wing-Man Yung W, Mackay J, Zhou R, Ferrari V, Gruber P, Epstein JA. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J Clin Invest. 2003;112(6):863–71. doi:10.1172/JCI19137.

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Kee HJ, Sohn IS, Nam KI, Park JE, Qian YR, Yin Z, Ahn Y, Jeong MH, Bang YJ, Kim N, Kim JK, Kim KK, Epstein JA, Kook H. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation. 2006;113(1):51–9. doi:10.1161/CIRCULATIONAHA.105.559724.

    CAS  PubMed  Google Scholar 

  106. Kong Y, Tannous P, Lu G, Berenji K, Rothermel BA, Olson EN, Hill JA. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation. 2006;113(22):2579–88. doi:10.1161/CIRCULATIONAHA.106.625467.

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Cardinale JP, Sriramula S, Pariaut R, Guggilam A, Mariappan N, Elks CM, Francis J. HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. Hypertension. 2010;56(3):437–44. doi:10.1161/HYPERTENSIONAHA.110.154567.

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Xie M, Kong Y, Tan W, May H, Battiprolu PK, Pedrozo Z, Wang ZV, Morales C, Luo X, Cho G, Jiang N, Jessen ME, Warner JJ, Lavandero S, Gillette TG, Turer AT, Hill JA. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation. 2014;129(10):1139–51. doi:10.1161/CIRCULATIONAHA.113.002416.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Loirand G, Sauzeau V, Pacaud P. Small G proteins in the cardiovascular system: physiological and pathological aspects. Physiol Rev. 2013;93(4):1659–720. doi:10.1152/physrev.00021.2012.

    CAS  PubMed  Google Scholar 

  110. Cherfils J, Zeghouf M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev. 2013;93(1):269–309. doi:10.1152/physrev.00003.2012.

    CAS  PubMed  Google Scholar 

  111. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006;7(8):589–600.

    CAS  PubMed  Google Scholar 

  112. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008;29(8):992–1006. doi:10.1002/humu.20748.

    CAS  PubMed  Google Scholar 

  113. Hunter JJ, Tanaka N, Rockman HA, Ross Jr J, Chien KR. Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. J Biol Chem. 1995;270(39):23173–8.

    CAS  PubMed  Google Scholar 

  114. Xu J, Ismat FA, Wang T, Lu MM, Antonucci N, Epstein JA. Cardiomyocyte-specific loss of neurofibromin promotes cardiac hypertrophy and dysfunction. Circ Res. 2009;105(3):304–11. doi:10.1161/CIRCRESAHA.109.201509.

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Harris IS, Zhang S, Treskov I, Kovacs A, Weinheimer C, Muslin AJ. Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation. 2004;110(6):718–23. doi:10.1161/01.CIR.0000138190.50127.6A.

    CAS  PubMed  Google Scholar 

  116. Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, Hikoso S, Hirotani S, Asahi M, Taniike M, Nakai A, Tsujimoto I, Matsumura Y, Miyazaki J, Chien KR, Matsuzawa A, Sadamitsu C, Ichijo H, Baccarini M, Hori M, Otsu K. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest. 2004;114(7):937–43. doi:10.1172/JCI20317.

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev. 2010;90(4):1507–46. doi:10.1152/physrev.00054.2009.

    CAS  PubMed  Google Scholar 

  118. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for Galphaq and alpha1-adrenergic receptor signaling in cardiomyocytes. Dissociation of Ras and Rho pathways. J Biol Chem. 1996;271(49):31185–90.

    CAS  PubMed  Google Scholar 

  119. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of Rho kinase. J Biol Chem. 1998;273(13):7725–30.

    CAS  PubMed  Google Scholar 

  120. Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn 2nd GW, Ross Jr J, Chien KR, Brown JH. Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure. J Clin Invest. 1999;103(12):1627–34. doi:10.1172/JCI6842.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Rikitake Y, Oyama N, Wang CY, Noma K, Satoh M, Kim HH, Liao JK. Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1+/- haploinsufficient mice. Circulation. 2005;112(19):2959–65. doi:10.1161/CIRCULATIONAHA.105.584623.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Yang X, Li Q, Lin X, Ma Y, Yue X, Tao Z, Wang F, McKeehan WL, Wei L, Schwartz RJ, Chang J. Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1. FASEB J. 2012;26(5):2105–16. doi:10.1096/fj.11-201319.

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106(12):1798–806. doi:10.1161/CIRCRESAHA.110.219840.

    CAS  PubMed  Google Scholar 

  124. Dawson K, Aflaki M, Nattel S. Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential. J Physiol. 2013;591(Pt 6):1409–32. doi:10.1113/jphysiol.2012.235382.

    PubMed Central  PubMed  Google Scholar 

  125. Haq S, Michael A, Andreucci M, Bhattacharya K, Dotto P, Walters B, Woodgett J, Kilter H, Force T. Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth. Proc Natl Acad Sci U S A. 2003;100(8):4610–5. doi:10.1073/pnas.0835895100.

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K, Kemler R. Lack of beta-catenin affects mouse development at gastrulation. Development. 1995;121(11):3529–37.

    CAS  PubMed  Google Scholar 

  127. Qu J, Zhou J, Yi XP, Dong B, Zheng H, Miller LM, Wang X, Schneider MD, Li F. Cardiac-specific haploinsufficiency of beta-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction. J Mol Cell Cardiol. 2007;43(3):319–26. doi:10.1016/j.yjmcc.2007.06.006.

    PubMed Central  CAS  PubMed  Google Scholar 

  128. Chen X, Shevtsov SP, Hsich E, Cui L, Haq S, Aronovitz M, Kerkela R, Molkentin JD, Liao R, Salomon RN, Patten R, Force T. The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy. Mol Cell Biol. 2006;26(12):4462–73. doi:10.1128/MCB. 02157-05.

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Baurand A, Zelarayan L, Betney R, Gehrke C, Dunger S, Noack C, Busjahn A, Huelsken J, Taketo MM, Birchmeier W, Dietz R, Bergmann MW. Beta-catenin downregulation is required for adaptive cardiac remodeling. Circ Res. 2007;100(9):1353–62. doi:10.1161/01.RES.0000266605.63681.5a.

    CAS  PubMed  Google Scholar 

  130. van de Schans VA, van den Borne SW, Strzelecka AE, Janssen BJ, van der Velden JL, Langen RC, Wynshaw-Boris A, Smits JF, Blankesteijn WM. Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy. Hypertension. 2007;49(3):473–80. doi:10.1161/01.HYP.0000255946.55091.24.

    PubMed  Google Scholar 

  131. Malekar P, Hagenmueller M, Anyanwu A, Buss S, Streit MR, Weiss CS, Wolf D, Riffel J, Bauer A, Katus HA, Hardt SE. Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling. Hypertension. 2010;55(4):939–45. doi:10.1161/HYPERTENSIONAHA.109.141127.

    CAS  PubMed  Google Scholar 

  132. Zhang Y, Liu Y, Zhu XH, Zhang XD, Jiang DS, Bian ZY, Zhang XF, Chen K, Wei X, Gao L, Zhu LH, Yang Q, Fan GC, Lau WB, Ma X, Li H. Dickkopf-3 attenuates pressure overload-induced cardiac remodelling. Cardiovasc Res. 2014;102(1):35–45. doi:10.1093/cvr/cvu004.

    CAS  PubMed  Google Scholar 

  133. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–41. doi:10.1016/j.cell.2011.10.026.

    CAS  PubMed  Google Scholar 

  134. Boya P, Reggiori F, Codogno P. Emerging regulation and functions of autophagy. Nat Cell Biol. 2013;15(7):713–20. doi:10.1038/ncb2788.

    CAS  PubMed  Google Scholar 

  135. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–6. nature03029 [pii].

    CAS  PubMed  Google Scholar 

  136. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004;15(3):1101–11. doi:10.1091/mbc.E03-09-0704. E03-09-0704 [pii].

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Kanamori H, Takemura G, Maruyama R, Goto K, Tsujimoto A, Ogino A, Li L, Kawamura I, Takeyama T, Kawaguchi T, Nagashima K, Fujiwara T, Fujiwara H, Seishima M, Minatoguchi S. Functional significance and morphological characterization of starvation-induced autophagy in the adult heart. Am J Pathol. 2009;174(5):1705–14. doi:10.2353/ajpath.2009.080875. ajpath.2009.080875 [pii].

    PubMed Central  CAS  PubMed  Google Scholar 

  138. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112(12):1809–20. doi:10.1172/JCI20039.

    PubMed Central  CAS  PubMed  Google Scholar 

  139. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169(3):425–34. doi:10.1083/jcb.200412022.

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, Omiya S, Mizote I, Matsumura Y, Asahi M, Nishida K, Hori M, Mizushima N, Otsu K. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 2007;13(5):619–24. doi:10.1038/nm1574. nm1574 [pii].

    CAS  PubMed  Google Scholar 

  141. Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, Le V, Levine B, Rothermel BA, Hill JA. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest. 2007;117(7):1782–93. doi:10.1172/JCI27523.

    PubMed Central  CAS  PubMed  Google Scholar 

  142. Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klovekorn WP, Schaper J. Myocytes die by multiple mechanisms in failing human hearts. Circ Res. 2003;92(7):715–24. doi:10.1161/01.RES.0000067471.95890.5C. 01.RES.0000067471.95890.5C [pii].

    CAS  PubMed  Google Scholar 

  143. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15(1):7–21. doi:10.1038/nrg3606.

    CAS  PubMed  Google Scholar 

  144. Liu N, Olson EN. MicroRNA regulatory networks in cardiovascular development. Dev Cell. 2010;18(4):510–25. doi:10.1016/j.devcel.2010.03.010.

    PubMed Central  CAS  PubMed  Google Scholar 

  145. van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson JA, Olson EN. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006;103(48):18255–60. doi:10.1073/pnas.0608791103.

    PubMed Central  PubMed  Google Scholar 

  146. Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res. 2007;100(3):416–24. doi:10.1161/01.RES.0000257913.42552.23.

    CAS  PubMed  Google Scholar 

  147. Leptidis S, El Azzouzi H, Lok SI, de Weger R, Olieslagers S, Kisters N, Silva GJ, Heymans S, Cuppen E, Berezikov E, De Windt LJ, da Costa Martins P. A deep sequencing approach to uncover the miRNOME in the human heart. PLoS One. 2013;8(2):e57800. doi:10.1371/journal.pone.0057800.

    PubMed Central  CAS  PubMed  Google Scholar 

  148. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9. doi:10.1038/ncb1596.

    CAS  PubMed  Google Scholar 

  149. Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L, Xiao T, Schafer J, Lee ML, Schmittgen TD, Nana-Sinkam SP, Jarjoura D, Marsh CB. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One. 2008;3(11):e3694. doi:10.1371/journal.pone.0003694.

    PubMed Central  PubMed  Google Scholar 

  150. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL, Tait JF, Tewari M. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011;108(12):5003–8. doi:10.1073/pnas.1019055108.

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13(4):423–33. doi:10.1038/ncb2210.

    PubMed Central  CAS  PubMed  Google Scholar 

  152. Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res. 2012;110(3):483–95. doi:10.1161/CIRCRESAHA.111.247452.

    CAS  PubMed  Google Scholar 

  153. van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science. 2007;316(5824):575–9. doi:10.1126/science.1139089.

    PubMed  Google Scholar 

  154. Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP, Chen JF, Deng Z, Gunn B, Shumate J, Willis MS, Selzman CH, Wang DZ. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009;119(9):2772–86. doi:10.1172/JCI36154.

    PubMed Central  CAS  PubMed  Google Scholar 

  155. Morkin E. Control of cardiac myosin heavy chain gene expression. Microsc Res Tech. 2000;50(6):522–31. doi:10.1002/1097-0029(20000915)50:6<522::AID-JEMT9>3.0.CO;2-U.

    CAS  PubMed  Google Scholar 

  156. van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm Jr RJ, Olson EN. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell. 2009;17(5):662–73. doi:10.1016/j.devcel.2009.10.013.

    PubMed Central  PubMed  Google Scholar 

  157. Shieh JT, Huang Y, Gilmore J, Srivastava D. Elevated miR-499 levels blunt the cardiac stress response. PLoS One. 2011;6(5):e19481. doi:10.1371/journal.pone.0019481.

    PubMed Central  CAS  PubMed  Google Scholar 

  158. Mathiyalagan P, Okabe J, Chang L, Su Y, Du XJ, El-Osta A. The primary microRNA-208b interacts with Polycomb-group protein, Ezh2, to regulate gene expression in the heart. Nucleic Acids Res. 2014;42(2):790–803. doi:10.1093/nar/gkt896.

    PubMed Central  CAS  PubMed  Google Scholar 

  159. Montgomery RL, Hullinger TG, Semus HM, Dickinson BA, Seto AG, Lynch JM, Stack C, Latimer PA, Olson EN, van Rooij E. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation. 2011;124(14):1537–47. doi:10.1161/CIRCULATIONAHA.111.030932.

    PubMed Central  CAS  PubMed  Google Scholar 

  160. Wang JX, Jiao JQ, Li Q, Long B, Wang K, Liu JP, Li YR, Li PF. MiR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med. 2011;17(1):71–8. doi:10.1038/nm.2282.

    PubMed  Google Scholar 

  161. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007;129(2):303–17. doi:10.1016/j.cell.2007.03.030.

    CAS  PubMed  Google Scholar 

  162. Ikeda S, He A, Kong SW, Lu J, Bejar R, Bodyak N, Lee KH, Ma Q, Kang PM, Golub TR, Pu WT. MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Mol Cell Biol. 2009;29(8):2193–204. doi:10.1128/MCB. 01222-08.

    PubMed Central  CAS  PubMed  Google Scholar 

  163. Ai J, Zhang R, Gao X, Niu HF, Wang N, Xu Y, Li Y, Ma N, Sun LH, Pan ZW, Li WM, Yang BF. Overexpression of microRNA-1 impairs cardiac contractile function by damaging sarcomere assembly. Cardiovasc Res. 2012;95(3):385–93. doi:10.1093/cvr/cvs196.

    CAS  PubMed  Google Scholar 

  164. Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, Bassel-Duby R, Olson EN. MicroRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 2008;22(23):3242–54. doi:10.1101/gad.1738708.

    PubMed Central  CAS  PubMed  Google Scholar 

  165. Care A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MV, Hoydal M, Autore C, Russo MA, Dorn 2nd GW, Ellingsen O, Ruiz-Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007;13(5):613–8. doi:10.1038/nm1582.

    CAS  PubMed  Google Scholar 

  166. Dong DL, Chen C, Huo R, Wang N, Li Z, Tu YJ, Hu JT, Chu X, Huang W, Yang BF. Reciprocal repression between microRNA-133 and calcineurin regulates cardiac hypertrophy: a novel mechanism for progressive cardiac hypertrophy. Hypertension. 2010;55(4):946–52. doi:10.1161/HYPERTENSIONAHA.109.139519.

    CAS  PubMed  Google Scholar 

  167. Ucar A, Gupta SK, Fiedler J, Erikci E, Kardasinski M, Batkai S, Dangwal S, Kumarswamy R, Bang C, Holzmann A, Remke J, Caprio M, Jentzsch C, Engelhardt S, Geisendorf S, Glas C, Hofmann TG, Nessling M, Richter K, Schiffer M, Carrier L, Napp LC, Bauersachs J, Chowdhury K, Thum T. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun. 2012;3:1078. doi:10.1038/ncomms2090.

    PubMed Central  PubMed  Google Scholar 

  168. Ni YG, Berenji K, Wang N, Oh M, Sachan N, Dey A, Cheng J, Lu G, Morris DJ, Castrillon DH, Gerard RD, Rothermel BA, Hill JA. Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation. 2006;114(11):1159–68. doi:10.1161/CIRCULATIONAHA.106.637124.

    PubMed Central  CAS  PubMed  Google Scholar 

  169. Li HH, Kedar V, Zhang C, McDonough H, Arya R, Wang DZ, Patterson C. Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J Clin Invest. 2004;114(8):1058–71. doi:10.1172/JCI22220.

    PubMed Central  CAS  PubMed  Google Scholar 

  170. Latronico MV, Condorelli G. MicroRNAs and cardiac pathology. Nat Rev Cardiol. 2009;6(6):419–29. doi:10.1038/nrcardio.2009.56.

    PubMed  Google Scholar 

  171. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469(7330):336–42. doi:10.1038/nature09783.

    PubMed Central  CAS  PubMed  Google Scholar 

  172. Kumarswamy R, Thum T. Non-coding RNAs in cardiac remodeling and heart failure. Circ Res. 2013;113(6):676–89. doi:10.1161/CIRCRESAHA.113.300226.

    CAS  PubMed  Google Scholar 

  173. Ulitsky I, Bartel DP. LincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154(1):26–46. doi:10.1016/j.cell.2013.06.020.

    PubMed Central  CAS  PubMed  Google Scholar 

  174. Grote P, Wittler L, Hendrix D, Koch F, Wahrisch S, Beisaw A, Macura K, Blass G, Kellis M, Werber M, Herrmann BG. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell. 2013;24(2):206–14. doi:10.1016/j.devcel.2012.12.012.

    PubMed Central  CAS  PubMed  Google Scholar 

  175. Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 2013;152(3):570–83. doi:10.1016/j.cell.2013.01.003.

    PubMed Central  CAS  PubMed  Google Scholar 

  176. Matkovich SJ, Edwards JR, Grossenheider TC, de Guzman Strong C, Dorn 2nd GW. Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs. Proc Natl Acad Sci U S A. 2014;111(33):12264–9. doi:10.1073/pnas.1410622111.

    PubMed Central  CAS  PubMed  Google Scholar 

  177. Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun T, Zhang XJ, Li PF. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res. 2014;114(9):1377–88. doi:10.1161/CIRCRESAHA.114.302476.

    CAS  PubMed  Google Scholar 

  178. Han P, Li W, Lin CH, Yang J, Shang C, Nurnberg ST, Jin KK, Xu W, Lin CY, Lin CJ, Xiong Y, Chien HC, Zhou B, Ashley E, Bernstein D, Chen PS, Chen HS, Quertermous T, Chang CP. A long noncoding RNA protects the heart from pathological hypertrophy. Nature. 2014;514(7520):102–6. doi:10.1038/nature13596.

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Hsu MT, Coca-Prados M. Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature. 1979;280(5720):339–40.

    CAS  PubMed  Google Scholar 

  180. Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012;7(2):e30733. doi:10.1371/journal.pone.0030733.

    PubMed Central  CAS  PubMed  Google Scholar 

  181. Capel B, Swain A, Nicolis S, Hacker A, Walter M, Koopman P, Goodfellow P, Lovell-Badge R. Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell. 1993;73(5):1019–30.

    CAS  PubMed  Google Scholar 

  182. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495(7441):384–8. doi:10.1038/nature11993.

    CAS  PubMed  Google Scholar 

  183. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–8. doi:10.1038/nature11928.

    CAS  PubMed  Google Scholar 

  184. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):145–53. doi:10.1056/NEJM200001203420301.

    CAS  PubMed  Google Scholar 

  185. Mathew J, Sleight P, Lonn E, Johnstone D, Pogue J, Yi Q, Bosch J, Sussex B, Probstfield J, Yusuf S, Heart Outcomes Prevention Evaluation I. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation. 2001;104(14):1615–21.

    CAS  PubMed  Google Scholar 

  186. Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, Rokkedal J, Harris K, Aurup P, Dahlof B. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA. 2004;292(19):2350–6. doi:10.1001/jama.292.19.2350.

    CAS  PubMed  Google Scholar 

  187. Chaanine AH, Kalman J, Hajjar RJ. Cardiac gene therapy. Semin Thorac Cardiovasc Surg. 2010;22(2):127–39. doi:10.1053/j.semtcvs.2010.09.009.

    PubMed Central  PubMed  Google Scholar 

  188. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ, Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease I. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation. 2011;124(3):304–13. doi:10.1161/CIRCULATIONAHA.111.022889.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine III – Cardiology and Angiology, University Medical Center of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany

    Christian Kuhn MD, Susanne Hille & Norbert Frey MD

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  1. Christian Kuhn MD
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  2. Susanne Hille
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  3. Norbert Frey MD
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  1. Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, Maryland, USA

    Gowraganahalli Jagadeesh

  2. Pharmacology Unit, AIMST University, Bedong, Malaysia

    Pitchai Balakumar

  3. Center for Drug Evaluation and Research Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, Maryland, USA

    Khin Maung-U

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Kuhn, C., Hille, S., Frey, N. (2015). Molecular Targets in the Treatment of Cardiac Hypertrophy. In: Jagadeesh, G., Balakumar, P., Maung-U, K. (eds) Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Adis, Cham. https://doi.org/10.1007/978-3-319-15961-4_18

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