Adult cardiac disease is the most frequent cause of mortality in the western world where death, as a result of heart failure, is more prevalent than all cancers combined(1). Heart failure can be defined as a deficiency in the ability of the heart to pump an adequate supply of blood around the body. The initial stimulus for progression along this pathway can be wide-ranging; congenital malformations; myocardial infarction, hypertension, myocarditis, diabetic cardiomyopathy, ischaemia associated with coronary artery disease, familial hypertrophic and dilated cardiomyopathies(2, 3, 4). Following the stimulus, there is normally a phase of cardiac hypertrophy whereby individual cardiac myocytes increase in size as a means of compensating for damaged heart tissue in order to increase cardiac pump function. In the long term however, such cardiac hypertrophy can predispose towards heart failure(4, 5, 6).
2. Pathological and physiological hypertrophy
Hypertrophy can be dissected into three distinct classifications:
The growth seen with developmental and physiological hypertrophy is morphologically distinguishable from that seen in pathological hypertrophy. Whereas in developmental and physiological hypertrophy, the growth of the cardiac myocytes and hence the ventricular wall and septum is comparable with an increase in chamber dimension, in pathological hypertrophy, the ventricular wall and septum thicken but with a concomitant decrease in ventricular chamber dimension. Pathological hypertrophy frequently progresses to dilated cardiomyopathy, which may be due, at least in part, to activation of apoptotic pathways(7).
In recent years, the identification and characterization of the molecular pathways leading to cardiac hypertrophy has highlighted a number of potential therapeutic targets. The prospective commercial market for novel drugs to treat cardiac hypertrophy is huge.
Pathological and physiological hypertrophic response to stimuli
3. Molecular regulators of cardiac hypertrophy
3.1 Contractile molecules
Cardiac hypertrophy is associated with increased expression of cardiac myocytes contractile molecules, regulated at both the transcriptional and translational level. Key players, with enhanced promoter and/or protein expression include β-myosin heavy chain (β-MHC), and other modulators such as atrial natriuretic protein (ANP), B-type natriuretic protein (BNP), and the α-skeletal muscle isoform of actin (αSA)(8, 9, 10). Alterations in these key control proteins (ANP,BNP) and cytoskeletal proteins (β/α-MHC, αSA) increase the load and subsequent pumping potential of the heart. However, a net increased intracellular viscosity limits the efficiency of this effort leading to cardiac myocyte hypertrophy(11, 12).
3.2 Cardiomyocyte gene expression
Hypertrophic growth involves control of cardiomyocyte gene expression at multiple molecular levels. Master regulators of gene expression in cardiac myocytes such as myoD,MEF2, and members of theGATAfamily(13, 14, 15), use histone acetyltransferases (HATs) and histone deacetylases (HDACs) to remodel chromatin as part of the mechanism by which they control gene expression(16, 17, 18). Recent work from our group and others has demonstrated that acetylation of histones alters gene expression in cardiac cells and response to pharmacologically induced-hypertrophy and simulated-ischaemia and reperfusion(7, 17, 19). Acetylation of histones is thought to lead to alterations in gene expression by relaxing chromatin (i.e., the packaging of DNA) and is catalysed byHATs. By contrast,HDACs mediate the removal of acetyl-groups.HDACs have been shown to be important endpoint targets of cell-signaling pathways involved in the induction of altered gene expression in cardiac hypertrophy and ischaemia/reperfusion injury(20)and are undergoing intense investigation as possible therapeutic regulators of hypertrophy-associated cardiac disease.
3.3 The HDAC family in hypertrophy
There are more than a dozen individualHDACenzymes which can be divided into three main classes - class IHDACs(HDACs 1, 2, 3, and 8), class IIHDACs(HDACs 4, 5, 6, 7, 9, and 10) and class IIISirT 1-X. Class III are distinguished from class I and II as they are NADH dependent enzymes(21).
In adult cardiac myocytes activation of theMEF2transcription factor in response to stress signaling activates a pro-hypertrophic gene expression profile. Stress signalling activatesMEF2by causing the nuclear export of class II histone deacetylases (HDACs), possibly regulated through protein kinase D(22), which would normally associate withMEF2and suppress its activity in normal cells. Thus, class IIHDACsplay a key role in suppression of hypertrophy(14, 23, 24). Consistent with this notion, mice lackingHDAC9orHDAC5, both class IIHDACs, are supersensitive to stress signals and both mouse models showed enhanced hypertrophy in response to pathological stimuli(25, 26). In contrast, class IHDACsare considered to play a pro-hypertrophic role, although the relevant gene targets are less well described(18, 27). Taken together, class I and IIHDACsplay opposing roles in control of hypertrophy and there is a clear benefit to the development of class IHDACspecific inhibitors as therapeutic agents, which would not interfere with the class II dependent inhibition of pro-hypertrophic pathways governed by factors such as MEF2 (see figure). See all the HDAC antibodies
Regulation of cardiac hypertrophy
Class I and IIHDACs play key opposing roles in modulating cardiac hypertrophy in CHD. Class IIHDACs are thought to repress whereas Class IHDACs induce pro-hypertrophic genes. A novel molecular therapy would aim to target and inhibit Class IHDACs thereby regulating cardiac hypertrophy.
4. Class selective HDAC inhibitors
The demonstration of separate classes ofHDACs which can regulate pro- and anti-hypertrophy genes underpins the use of class selective inhibitors ofHDACs(especially those that target class I enzymes). The clinical use ofHDACinhibitors would allow the control of key hypertrophic genes, and would provide a novel molecular and therapeutic approach.
HDACinhibitors have progressed well as experimental therapeutic agents for the treatment of cancer, but most of these agents are non-selective. By contrast, the bicyclic tetrapeptideHDACinhibitors FK228 and Spiruchostatin A appear to possess selectivity towards class IHDACs(28 and unpublished data). This activity profile may make them particularly attractive as starting points to develop novel therapies for cardiovascular disease. Indeed, it has already been shown that Spiruchostatin A is a highly potent inhibitor (~pM) ofHDACs in cardiac myocytes and effectively interferes with the pro-hypertrophic effects of phenylephrine and urocortin(17).
Dissection and characterization of the signaling pathways leading to cardiac hypertrophy has led to a wealth of knowledge about this condition both physiological and pathological(29). Although these pathways have still to be defined further and there will undoubtedly be future pathways and players to be discovered; the challenge currently will be to translate this scientific knowledge and understanding into potential pharmacological therapies for the treatment of pathological cardiac hypertrophy.
1. Scarabelli, T.M., Knight, R., Stephanou, A., Townsend, P.A., Chen-Scarabelli, C., Lawrence, K., Gottlieb, R., Latchman, D., and Narula, J. Clinical implications of apoptosis in ischemic myocardium. Current Problems in Cardiology, 31, 181-264, 2006.
2. Klein L, O'Connor CM, Gattis WA, Zampino M, de Luca L, Vitarelli A, Fedele F, and Gheorghiade M. Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations. Am J Cardiol. 2003, 91(9A):18F-40F
3. Lips DJ, deWindt LJ, van Kraaij DJ, Doevendans PA. Molecular determinants of myocardial hypertrophy and failure: alternative pathways for beneficial and maladaptive hypertrophy. Eur Heart J. 2003, 24(10):883-96
4. Heineke J, and Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006, 7(8):589-600
5. Haider AW, Larson MG, Benjamin EJ, and Levy D. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol. 1998, 32(5):1454-9
6. Berenji K, Drazner MH, Rothermel BA, and Hill JA Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol. 2005, 289(1):H8-H16
7. Davidson, S.M., Townsend, P.A., Stephanou, A., Packham, G., and Latchman, D.S. Inhibitors of p300 HAT activity or HDACs can dissociate the hypertrophic and protective pathways in cardiac myocytes: divergent effects of urocortin and phenylephrine. ChemBioChem, 2005, 6:162-170.
8. Abraham WT, Gilbert EM, Lowes BD, Minobe WA, Larrabee P, Roden RL, Dutcher D, Sederberg J, Lindenfeld JA, Wolfel EE, Shakar SF, Ferguson D, Volkman K, Linseman JV, Quaife RA, Robertson AD, and Bristow MR Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype. Mol. Med. 2002, 8:750–760
9. Olson, E.N. and Schneider, M.D. Sizing up the heart: development redux in disease. Genes Dev. 2003, 17:1937–1956
10. Akazawa, H. and Komuro, I. Roles of cardiac transcription factors in cardiac hypertrophy. Circ. Res. 2003, 92:1079-1088
11. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, and Maeda N. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J. Clin. Invest. 2001, 107:975–984
12. Holtwick R, van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, and Kuhn M. Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J. Clin. Invest. 2003, 111:1399–1407
13. Chanalaris, A., Lawrence, K.M., Townsend, P.A., Davidson, S., Jamshidi, Y., Stephanou, A., Knight, R.A., Hsu, S.Y., Hsueh, A.J., and Latchman, D.S. Hypertrophic effects of urocortin homologous peptides are mediated via activation of the Akt pathway. Biochem Biophys Res Commun. 2005, 328:442-8
14. Kolodziejczyk S.M., Wang L., Balazsi K., DeRepentigny Y., Kothary R., and Megeney L.A. MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium. Current Biology 1999, 9(20): 1203-1206
15. Liang Q., and Molkentin, J.D. Divergent signalling pathways converge on GATA4 to regulate cardiac hypertrophic gene expression. J. Mol. Cell. Cardiol. 2002, 34:611-616
16. Lu, J., McKinsey, T.A., Nicol, R.L., and Olson, E.N. Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc. Natl. Acad. Sci. 2000, 97: 4070–4075
17. Davis FJ, Pillai JB, Gupta M, and Gupta MP. Concurrent opposite effects of an inhibitor of histone deacetylases, Trichostatin-A, on the expression of α-myosin heavy chain and cardiac tubulins: Implications for gain in cardiac muscle contractility. American J. of Physiology (Heart and Circulation Physiology) In Press.
18. Townsend, P.A., Davidson, S.M., Crabb, S.J., Packham, G. and Ganesan, A. The Bicyclic Depsipeptide Family of Histone Deacetylase Inhibitors. In: Chemical Biology (Schreiber, Kapoor and Wess Eds.). In press, 2007
19. McKinsey T.A. Dual roles of histone deacetylases in the control of cardiac growth. Novartis Foundation Symposium, 2004, 259, 132-141
20. Frey N, Katus HA, Olson EN, and Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation, 2004, 109:1580-1589
21. De Ruijter, A.J., van Gennip, A.H., Caron, H. H., Kemp, S. and van Kuilenburg, A.B. Histone deacetylases (HDACs): Characterisation of the classical HDAC family. Biochem. J. 2003, 370:737-749
22. Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, and 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
23. Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, and Kouzarides T. HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J. 1999, 18:5099-5107
24. Lu, J., McKinsey, T.A., Nicol, R. L., and Olson, E.N. Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc. Natl. Acad. Sci. USA 2000, 97:4070-4075
25. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, and Olson EN. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 2002, 110:479-488
26. 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, 24:8467-8476
27. McKinsey T.A. and Olson E.N. Cardiac histone acetylation – therapeutic opportunities abound. Trends in Genetics 2004, 20:206-213
28. Crabb, S.J, Rogers, H. Townsend, P.A., Johnson, P.W.M., Shin-ya, Ganesan, A., and Packham, G. Bicyclic tetrapeptide histone deacetylase inhibitors FK228 and Spiruchostatin A induce delayed and protracted histone acetylation. In Press Molecular cancer Therapeutics, 2007
29. Heineke, J. and Molkentin, J.D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev. Mol Cell Biol. 2006, 7:589-600
Get resources and offers direct to your inboxSign up