Abstract 12479: Delayed Tranilast Treatment Reduces Pathological Fibrosis Following Myocardial Infarction And In Uremic Cardiomyopathy
Background: Cardiac fibrosis contributes to heart failure progression following myocardial infarction (MI) and chronic kidney disease (uremic cardiomyopathy). We examined the effect of the anti-fibrotic agent, tranilast, on cardiac fibrosis in both heart and kidney failure.
Methods: MI was induced by coronary artery ligation in Sprague Dawley (SD) rats, and animals randomized to receive tranilast (300mg/kg/day, p.o.) or vehicle for 28 days. Renal failure was induced by 5/6 nephrectomy (STNx) and animals randomized to receive tranilast (300mg/kg/day, p.o.) or vehicle for 12 weeks. Myocardial tissues were harvested for histological analysis. To determine direct effects of tranilast, cardiac fibrosis independent of any hemodynamic influence, neonatal cardiac fibroblasts (NCF) were stimulated with TGFβ1 in the presence and absence of tranilast and examined for proline incorporation, profibrotic gene and phospho-Smad2 protein expression.
Results: Tranilast treatment in MI animals attenuated the change in fractional shortening (FS) by 65% (change in FS: Sham +2.5±1.5%; MI+V -8.7±3.7%; MI+T -1.4±2.6%; P<0.05) versus V, and reduced collagen I and III deposition in the heart (Table). Macrophage infiltration was reduced in the NIZ (85%) and BZ (30%) (P<0.05), and TGFβ1 and CTGF gene expression was reduced in the NIZ with tranilast (P<0.05). Tranilast reduced collagen I and III deposition in the heart of STNx animals (Table; P<0.05). In NCF, tranilast reduced TGFβ1-stimulated proline incorporation, and collagen I, fibronectin and TGFβ1 gene expression (P<0.05). Phospho-Smad2 was reduced in NCF following tranilast treatment (by 65%, P<0.05).
Conclusion: Tranilast improved cardiac function post-MI, and reduced cardiac fibrosis post-MI and post-STNx. These effects appear to be mediated via tranilast's direct actions on NCF via the Phospho-Smad2 pathway, and in part by its anti-inflammatory effect.
- © 2011 by American Heart Association, Inc.