Copyright © 2004, European Society of Cardiology
Tranilast attenuates cardiac matrix deposition in experimental diabetes: role of transforming growth factor-β
aUniversity of Melbourne Department of Medicine, St. Vincent's Hospital, Victoria Australia
bUniversity of Melbourne Department of Physiology, St. Vincent's Hospital, Victoria Australia
cMonash University Department of Medicine, Alfred Hospital, Victoria Australia
* Corresponding author. Tel.: +61 3 9288 2580; fax: +61 3 9288 2581. Email address: gilbert{at}medstv.unimelb.edu.au
Objective: The pathological accumulation of extracellular matrix is a characteristic feature of diabetic cardiomyopathy that is directly related to a loss of function. Tranilast (n-[3,4-anthranilic acid), used for the treatment of fibrotic skin diseases, has also been shown to inhibit transforming growth factor-β (TGF-β)-induced matrix production in kidney epithelial cells.
Methods: To investigate the effects of tranilast in the diabetic heart, we examined its effects in cultured cardiac fibroblasts and then assessed its effects in (mRen-2)27 diabetic rats with established disease (8 weeks after streptozotocin).
Results: In vitro studies demonstrated a 58% reduction in TGF-β1-induced 3[H]-hydroxyproline incorporation with tranilast 30 µM (p<0.01). At 16 weeks, diabetes in the Ren-2 rat was associated with increased cardiac fibrosis and evidence of TGF-β1 activation, as measured by the abundance of phosphorylated Smad2. Despite persistent hyperglycaemia and hypertension, tranilast attenuated cardiac fibrosis by 37% (p<0.05) in association with reduction in phospho-Smad2 (p<0.01).
Conclusion: These findings indicate that tranilast has antifibrotic actions in the Ren-2 model of experimental diabetic cardiac disease by mechanisms that might attributable to reduced TGF-β activity.
KEYWORDS Fibrosis; Diabetes; Growth factors; Extracellular matrix
1 Authors contributed equally to this manuscript.
Time for primary review 29 days
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