Tranilast attenuates cardiac matrix deposition in experimental diabetes: role of transforming growth factor-beta.
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-beta (TGF-beta)-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-beta1-induced 3[H]-hydroxyproline incorporation with tranilast 30 microM (p<0.01). At 16 weeks, diabetes in the Ren-2 rat was associated with increased cardiac fibrosis and evidence of TGF-beta1 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).


CONCLUSIONS
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-beta activity.
Martin
Jennifer
J
University of Melbourne, Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
Kelly
Darren J
DJ
Mifsud
Sally A
SA
Zhang
Yuan
Y
Cox
Alison J
AJ
See
Fiona
F
Krum
Henry
H
Wilkinson-Berka
Jennifer
J
Gilbert
Richard E
RE
D000818:Animals; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use*
D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D062367:ortho-Aminobenzoates; D003094:Collagen; C012293:tranilast