Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension

Abstract

Background  

Growth factors such as transforming growth factor-beta (TGFβ) are believed to have an essential role in cardiac fibrosis. Tranilast (N (3,4-dimethoxycinnamoyl) anthranilic acid) attenuates the increased expression of TGFβ mRNA in vitro.

Objective  

To investigate whether tranilast reduces cardiac fibrosis in rats with two-kidney, one-clip (2K1C) renovascular hypertension. In addition, we tested the in-vitro effects of tranilast on cardiac myocytes and non-myocyte cells.

Methods  

We analysed hearts from four groups of rats: sham-operated controls; rats with 2K1C renovascular hypertension; rats with 2K1C renovascular hypertension treated for 12 weeks with the angiotensin converting enzyme (ACE) inhibitor, quinapril (6 mg/kg per day); rats with 2K1C renovascular hypertension treated for 12 weeks with tranilast (400 mg/kg per day).

Results  

Systolic blood pressure was reduced after quinapril treatment. Tranilast did not alter blood pressure (2K1C: 223 ± 19 mmHg; 2K1C + quinapril: 149 ± 15 mmHg (P< 0.01 compared with 2K1C); 2K1C + tranilast: 204 ± 32 mmHg). Left ventricular weight was likewise reduced significantly by quinapril, but not significantly by tranilast (2K1C: 1.52 ± 0.2 g; 2K1C + quinapril: 1.26 ± 0.18 g (P< 0.05 compared with 2K1C); 2K1C + tranilast: 1.37 ± 0.27 g). Using a computer-aided image analysis system, we demonstrated that tranilast prevented cardiac fibrosis in a blood-pressure-independent manner (P< 0.01 compared with 2K1C). Determination of the cardiac hydroxyproline content similarly revealed a significant reduction in cardiac fibrosis by tranilast (2K1C: 4.92 ± 0.48 mg/mg; 2K1C + tranilast: 3.97 ± 0.46 mg/mg;P< 0.05). The effect of tranilast on cardiac fibrosis was comparable to the effects of a blood-pressure-decreasing dose of the ACE inhibitor, quinapril. Cell culture experiments revealed that tranilast significantly decreased the proliferation of cardiac non-myocyte cells. Proliferation of cardiac myocytes was not altered.

Conclusion  

This study revealed that long-term treatment with tranilast markedly attenuated left ventricular fibrosis in rats with renovascular hypertension. This was most probably the result of an antiproliferative effect of tranilast on cardiac non-myocyte cells. Tranilast thus offers a unique new therapeutic approach to the reduction of TGFβ-mediated cardiac fibrosis in vivo.