Tranilast Prevents Activation of Transforming Growth Factor-&bgr; System, Leukocyte Accumulation, and Neointimal Growth in Porcine Coronary Arteries After Stenting

Abstract

N (3,4-Dimethoxycinnamoyl) anthranilic acid (tranilast) prevents the synchronous upregulation of isoforms and receptors of the transforming growth factor (TGF)-&bgr; system after arterial injury and reduces restenosis after human coronary angioplasty. However, the effects of tranilast and the importance of the TGF-&bgr; system in stent restenosis, in which inward remodeling is unimportant but inflammatory cell stimulation of neointima formation is exaggerated, are uncertain. Boston minipigs, treated with tranilast or vehicle, were subjected to endoluminal stenting, and the expression of TGF-&bgr;1 and TGF-&bgr;3, the expression of their signaling receptors ALK-5 and T&bgr;R-II, leukocyte numbers around the stent struts, and neointima development were assessed over 28 days. Stenting greatly increased early (5-day) mRNA expression of the 2 TGF-&bgr; isoforms and their receptors. Immunohistochemical localization later showed that their concentrations were greatest in regions adjacent to stent struts, where leukocytes and collagen deposition were prevalent. Tranilast suppressed these elevations in TGF-&bgr; mRNAs and reduced their immunoreactive peptides detectable around stent struts. The accumulation of leukocytes and deposition of collagen in these regions was also greatly inhibited by tranilast. These effects were associated with a 48% reduction in maximal neointimal cross-sectional area and 43% reduction in mean neointimal cross-sectional area at 28 days (P <0.05). We conclude that tranilast suppresses neointima development after stenting, effects that can be at least partly attributed to its ability to attenuate the induction of the TGF-&bgr; system and leukocyte accumulation around stent struts.