• Jennifer Martin, Darren J Kelly, Sally A Mifsud, Yuan Zhang, Alison J Cox, Fiona See, Henry Krum, Jennifer Wilkinson-Berka, and Richard E Gilbert.
• University of Melbourne, Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
• Cardiovasc. Res. 2005 Feb 15; 65 (3): 694-701.

ObjectiveThe 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.MethodsTo 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).ResultsIn 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).ConclusionThese 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.

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