Abstract 10630: Active Myocardial TGF-β Level is Significantly Increased in End-Stage Human Heart Failure
Persistent TGF-β activation is thought to be involved in progressive ventricular remodeling and TGF-β inhibition has been considered as a potential treatment to prevent the progression of heart failure. However, there has been no direct evidence of increased active TGF-β levels in the diseased human myocardium. Thus, we assessed the hypothesis that increased active TGF-β is seen in the myocardium of end-stage heart failure. We examined the molecular and biochemical profiles of human myocardial tissues from non failing donors (NF; n = 10), patients with ischemic cardiomyopathy (ICM; n = 10) and non-ischemic cardiomyopathy (NICM; n = 10) obtained at the time of heart transplant. We studied mRNA levels by real-time RT-PCR, protein levels by immunoblots, and active TGF-β levels by bioassay using cultured mink lung epithelial cells transfected with plasminogen activator inhibitor (PAI)-1 promoter-luciferase construct. Using this assay, active TGF-β levels were measured in the protein extracts from myocardial tissues. Data were shown as mean ±SD. The patients' ages were NF 49± 20, ICM 57± 5, and NICM 52 ±10. Pre-transplant LVEF was NF 67 ±7%, ICM 21 ±14%, and NICM 14 ±6%. There was no significant difference in Collagen I, Collagen III, or TGF-β1 mRNA levels among the 3 groups. Although TGF-β1 protein levels by immunoblots were not significantly different in 3 groups, there was a pronounced increase in free TGF-β levels (Figure) and in phosphorylation of Smad2 in ICM and NICM compared with NF [NF 1.0 ±0.16; ICM 2.44 ±0.47 (p < 0.000005); NICM 2.45 ±0.74 (p < 0.0005)]. We demonstrated that biologically active myocardial TGF-β levels were significantly higher in ICM and NICM than in NF. In conclusion, our data suggest that an active myocardial TGF-β level may serve as a sensitive biomarker for the progression of heart failure and that TGF-β may be a target for future therapeutic interventions recognizing that failing human hearts have increased interstitial fibrosis.
- © 2011 by American Heart Association, Inc.