title: Enhanced bioactive myocardial transforming growth factor-β in advanced human heart failure.
abstract: BACKGROUND
  Transforming growth factor (TGF)-β activation is known to play a central role in progressive ventricular remodeling in advanced heart failure in animal models, but there has been no direct evidence of increased TGF-β activity in the myocardium of patients with advanced human heart failure. METHODS AND RESULTS: Using a recently developed bioassay that measures TGF-β bioactivity rather than TGF-β abundance, we measured bioactive TGF-β in human myocardium from control non-failing donors (NF), and patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). Both free and total soluble TGF-β were significantly increased in ICM and DCM compared with NF. Free TGF-β had an excellent correlation with phosphorylated Smad2 (R(2)=0.55, P<0.0001), a downstream marker of TGF-β signaling. Collagen type I and type III were significantly upregulated in DCM compared with NF, consistent with histological evidence of myocardial fibrosis. Expression of fibulin-2, a positive modulator of TGF-β, was significantly increased in DCM compared with NF, and the free TGF-β level was correlated with fibulin-2 mRNA (R(2)=0.24, P<0.006).
  
  
  CONCLUSIONS
  Although both free and total soluble TGF-β are significantly increased in ICM and DCM compared with NF, the superior correlation of free TGF-β with downstream signaling suggests that this is the most functionally relevant form. The present findings suggest that sustained TGF-β activation in both ICM and DCM contributes to excess myocardial fibrosis.
authors.affiliation: Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children.
authors.forename: Shaukat
authors.initials: S
authors.lastname: Khan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Joyce
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsuda
mesh_terms: D000293:Adolescent; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D009124:Muscle Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C084612:fibulin 2