title: Tranilast prevents activation of transforming growth factor-beta 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)-beta system after arterial injury and reduces restenosis after human coronary angioplasty. However, the effects of tranilast and the importance of the TGF-beta 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-beta1 and TGF-beta3, the expression of their signaling receptors ALK-5 and TbetaR-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-beta 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-beta 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-beta system and leukocyte accumulation around stent struts.
authors.affiliation: Cell Biology Laboratory, Baker Medical Research Institute, Prahran, Victoria, Australia. mrward@doh.health.nsw.gov.au
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ward
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
authors.forename: Peter
authors.initials: P
authors.lastname: Kanellakis
authors.forename: John
authors.initials: J
authors.lastname: Hall
authors.forename: Garry
authors.initials: G
authors.lastname: Jennings
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D023903:Coronary Restenosis / Q000517:prevention & control; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology / Q000601:surgery; D004334:Drug Administration Schedule; D006965:Hyperplasia / Q000473:pathology; D007249:Inflammation / Q000517:prevention & control; D007964:Leukocytosis / Q000517:prevention & control*; D008297:Male; D015607:Stents; D013552:Swine; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; C012293:tranilast