Fibronectin and transforming growth factor beta contribute to erythropoietin resistance and maladaptive cardiac hypertrophy

Morais, Christudas, Small, David M., Vesey, David A., Martin, Jennifer, Johnson, David W. and Gobe, Glenda C. (2014) Fibronectin and transforming growth factor beta contribute to erythropoietin resistance and maladaptive cardiac hypertrophy. Biochemical and Biophysical Research Communications, In Press, Corrected Proof 1-6. doi:10.1016/j.bbrc.2014.01.047


Author Morais, Christudas
Small, David M.
Vesey, David A.
Martin, Jennifer
Johnson, David W.
Gobe, Glenda C.
Title Fibronectin and transforming growth factor beta contribute to erythropoietin resistance and maladaptive cardiac hypertrophy
Journal name Biochemical and Biophysical Research Communications   Check publisher's open access policy
ISSN 0006-291X
1090-2104
Publication date 2014-01-22
Sub-type Article (original research)
DOI 10.1016/j.bbrc.2014.01.047
Volume In Press, Corrected Proof
Start page 1
End page 6
Total pages 6
Place of publication Maryland Heights, MO, United States
Publisher Elsevier
Collection year 2015
Language eng
Formatted abstract
Highlights
• Recombinant human Erythropoietin (EPO) is a double-edged sword.
• EPO could protect the heart through the suppression of fibronectin and TGF-β.
• EPO could also kill the heart though the up-regulation of fibronectin and TGF-β.

The use of recombinant human erythropoietin (rhEPO) to promote repair and minimize cardiac hypertrophy after myocardial infarction has had disappointing outcomes in clinical trials. We hypothesized that the beneficial non-hematopoietic effects of rhEPO against cardiac hypertrophy could be offset by the molecular changes initiated by rhEPO itself, leading to rhEPO resistance or maladaptive hypertrophy. This hypothesis was investigated using an isoproterenol-induced model of myocardial infarct and cardiac remodelling with emphasis on hypertrophy. In h9c2 cardiomyocytes, rhEPO decreased isoproterenol-induced hypertrophy, and the expression of the pro-fibrotic factors fibronectin, alpha smooth muscle actin and transforming growth factor beta-1 (TGF-β1). In contrast, by itself, rhEPO increased the expression of fibronectin and TGF-β1. Exogenous TGF-β1 induced a significant increase in hypertrophy, which was further potentiated by rhEPO. Exogenous fibronectin not only induced hypertrophy of cardiomyocytes, but also conferred resistance to rhEPO treatment. Based on these findings we propose that the outcome of rhEPO treatment for myocardial infarction is determined by the baseline concentrations of fibronectin and TGF-β1. If endogenous fibronectin or TGF-β levels are above a certain threshold, they could cause resistance to rhEPO therapy and enhancement of cardiac hypertrophy, respectively, leading to maladaptive hypertrophy.
Keyword Erythropoietin
Fibronectin
Hypertrophy
Isoproterenol
Transforming growth factor beta
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 22 January 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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Created: Tue, 04 Feb 2014, 21:37:23 EST by Dr Christudas Morais on behalf of Medicine - Princess Alexandra Hospital