Fibronectin and transforming growth factor beta contribute to erythropoietin resistance and maladaptive cardiac hypertrophy.
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.
Centre for Kidney Disease Research, School of Medicine, The University of Queensland at Translational Research Institute, Brisbane, Queensland 4102, Australia. Electronic address: c.morais@uq.edu.au.
Christudas
C
Morais
Centre for Kidney Disease Research, School of Medicine, The University of Queensland at Translational Research Institute, Brisbane, Queensland 4102, Australia. Electronic address: d.small@uq.edu.au.
David M
DM
Small
Centre for Kidney Disease Research, School of Medicine, The University of Queensland at Translational Research Institute, Brisbane, Queensland 4102, Australia; Department of Renal Medicine, The University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia. Electronic address: david.vesey@health.qld.gov.au.
David A
DA
Vesey
School of Medicine, The University of Queensland, Brisbane, Queensland 4102, Australia. Electronic address: j.martin4@uq.edu.au.
Jennifer
J
Martin
Centre for Kidney Disease Research, School of Medicine, The University of Queensland at Translational Research Institute, Brisbane, Queensland 4102, Australia; Department of Renal Medicine, The University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland 4102, Australia. Electronic address: David_Johnson@health.qld.gov.au.
David W
DW
Johnson
Centre for Kidney Disease Research, School of Medicine, The University of Queensland at Translational Research Institute, Brisbane, Queensland 4102, Australia. Electronic address: g.gobe@uq.edu.au.
Glenda C
GC
Gobe
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D002460:Cell Line; D004921:Erythropoietin / Q000494:pharmacology*; D005353:Fibronectins / Q000502:physiology*; D007545:Isoproterenol / Q000633:toxicity; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology*
D005353:Fibronectins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D004921:Erythropoietin; D007545:Isoproterenol
Erythropoietin; Fibronectin; Hypertrophy; Isoproterenol; Transforming growth factor beta