(Circulation. 2001;103:670.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Differential Activation of Signal Transduction Pathways in Human Hearts With Hypertrophy Versus Advanced Heart Failure
From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children’s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.).
Correspondence to Thomas Force, MD, Molecular Cardiology Research Institute, New England Medical Center, Box 8486, 750 Washington St, Boston, MA 02111. E-mail tforce{at}lifespan.org
Background—Left ventricular failure is commonly preceded by a period of hypertrophy. Intriguingly, many of the signaling pathways that have been implicated in the regulation of hypertrophy, including the 3 mitogen-activated protein kinases (MAPKs: extracellular signal-regulated kinase, stress-activated protein kinase, and p38), protein phosphatase, calcineurin, and the protein kinase Akt and its target glycogen synthase kinase-3 (GSK-3), also regulate the apoptotic response.
Methods and Results—To understand the mechanisms that might regulate the progression of heart failure, we analyzed the activity of these signaling pathways in the hearts of patients with advanced heart failure, patients with compensated cardiac hypertrophy, and normal subjects. In patients with hypertrophy, neither the MAPK nor the Akt/GSK-3 pathways were activated, and the dominant signaling pathway was calcineurin. In failing hearts, calcineurin activity was increased but less so than in the hypertrophied hearts, and all 3 MAPKs and Akt were activated (and, accordingly, GSK-3ß was inhibited), irrespective of whether the underlying diagnosis was ischemic or idiopathic cardiomyopathy.
Conclusions—In the failing heart, there is a clear prohypertrophic activity profile, likely occurring in response to increased systolic wall stress and neurohormonal mediators. However, with the activation of these hypertrophic pathways, potent proapoptotic and antiapoptotic signals may also be generated. Therapies directed at altering the balance of activity of these signaling pathways could potentially alter the progression of heart failure.
Key Words: calcineurin • cardiomyopathy • mitogen-activated protein kinases
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S. E. Hardt and J. Sadoshima Glycogen Synthase Kinase-3{beta}: A Novel Regulator of Cardiac Hypertrophy and Development Circ. Res., May 31, 2002; 90(10): 1055 - 1063. [Abstract] [Full Text] [PDF]
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B. J Wilkins and J. D Molkentin Calcineurin and cardiac hypertrophy: Where have we been? Where are we going? J. Physiol., May 15, 2002; 541(1): 1 - 8. [Abstract] [Full Text] [PDF]
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O. Ritter, S. Hack, K. Schuh, N. Rothlein, A. Perrot, K. J. Osterziel, H. D. Schulte, and L. Neyses Calcineurin in Human Heart Hypertrophy Circulation, May 14, 2002; 105(19): 2265 - 2269. [Abstract] [Full Text] [PDF]
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N. N Petrashevskaya, I. Bodi, M. Rubio, J. D Molkentin, and A. Schwartz Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse Cardiovasc Res, April 1, 2002; 54(1): 117 - 132. [Abstract] [Full Text] [PDF]
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Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]
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O. F. Bueno, B. J. Wilkins, K. M. Tymitz, B. J. Glascock, T. F. Kimball, J. N. Lorenz, and J. D. Molkentin Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice PNAS, March 19, 2002; (2002) 72647999. [Abstract] [Full Text] [PDF]
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O. F Bueno, E. van Rooij, J. D Molkentin, P. A Doevendans, and L. J De Windt Calcineurin and hypertrophic heart disease: novel insights and remaining questions Cardiovasc Res, March 1, 2002; 53(4): 806 - 821. [Abstract] [Full Text] [PDF]
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C. L. Antos, T. A. McKinsey, N. Frey, W. Kutschke, J. McAnally, J. M. Shelton, J. A. Richardson, J. A. Hill, and E. N. Olson Activated glycogen synthase-3beta suppresses cardiac hypertrophy in vivo PNAS, January 7, 2002; (2002) 231619298. [Abstract] [Full Text] [PDF]
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G. Esposito, A. Rapacciuolo, S. V. Naga Prasad, H. Takaoka, S. A. Thomas, W. J. Koch, and H. A. Rockman Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress Circulation, January 1, 2002; 105(1): 85 - 92. [Abstract] [Full Text] [PDF]
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M. Flesch, K. B. Margulies, H.-C. Mochmann, D. Engel, N. Sivasubramanian, and D. L. Mann Differential Regulation of Mitogen-Activated Protein Kinases in the Failing Human Heart in Response to Mechanical Unloading Circulation, November 6, 2001; 104(19): 2273 - 2276. [Abstract] [Full Text] [PDF]
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J. R. Woodgett Judging a Protein by More Than Its Name: GSK-3 Sci. Signal., September 18, 2001; 2001(100): re12 - re12. [Abstract] [Full Text] [PDF]
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G. Schwartzbauer and J. Robbins Matters of Sex: Sex Matters Circulation, September 18, 2001; 104(12): 1333 - 1335. [Full Text] [PDF]
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M. van Eickels, C. Grohe, J. P.M. Cleutjens, B. J. Janssen, H. J.J. Wellens, and P. A. Doevendans 17{beta}-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy Circulation, September 18, 2001; 104(12): 1419 - 1423. [Abstract] [Full Text] [PDF]
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O. F. Bueno, B. J. Wilkins, K. M. Tymitz, B. J. Glascock, T. F. Kimball, J. N. Lorenz, and J. D. Molkentin Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice PNAS, April 2, 2002; 99(7): 4586 - 4591. [Abstract] [Full Text] [PDF]
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C. L. Antos, T. A. McKinsey, N. Frey, W. Kutschke, J. McAnally, J. M. Shelton, J. A. Richardson, J. A. Hill, and E. N. Olson Activated glycogen synthase-3beta suppresses cardiac hypertrophy in vivo PNAS, January 22, 2002; 99(2): 907 - 912. [Abstract] [Full Text] [PDF]
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Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]
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R. Sah, G. Y. Oudit, T.-T. T. Nguyen, H. W. Lim, A. D. Wickenden, G. J. Wilson, J. D. Molkentin, and P. H. Backx Inhibition of Calcineurin and Sarcolemmal Ca2+ Influx Protects Cardiac Morphology and Ventricular Function in Kv4.2N Transgenic Mice Circulation, April 16, 2002; 105(15): 1850 - 1856. [Abstract] [Full Text] [PDF]
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