title: Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure.
abstract: 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.
  
  
  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.
authors.affiliation: Cardiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Haq
authors.forename: G
authors.initials: G
authors.lastname: Choukroun
authors.forename: H
authors.initials: H
authors.lastname: Lim
authors.forename: K M
authors.initials: KM
authors.lastname: Tymitz
authors.forename: F
authors.initials: F
authors.lastname: del Monte
authors.forename: J
authors.initials: J
authors.lastname: Gwathmey
authors.forename: L
authors.initials: L
authors.lastname: Grazette
authors.forename: A
authors.initials: A
authors.lastname: Michael
authors.forename: R
authors.initials: R
authors.lastname: Hajjar
authors.forename: T
authors.initials: T
authors.lastname: Force
authors.forename: J D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D019703:Calcineurin / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D008297:Male; D008875:Middle Aged; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D011518:Proto-Oncogene Proteins; D048056:Mitogen-Activated Protein Kinase 9; D038341:Glycogen Synthase Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin