(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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