Title

Suppression by mycophenolic acid (MPA) of balloon-induced vascular neointimal growth in rats

Date of Completion

January 2003

Keywords

Health Sciences, Pharmacology|Biology, Animal Physiology|Health Sciences, Medicine and Surgery

Degree

Ph.D.

Abstract

Restenosis has been a major complication that limits the long-term efficacy of Percutaneous Transluminal Coronary Angioplasty (PTCA). Studies from humans and animals have suggested an inflammatory response that leads to SMC proliferation may be involved in the pathogenesis of restenosis. The balloon injury to rat carotid artery provides an optimal model to examine the role of SMC proliferation in neointimal growth as well as the association of other possible contributing factors, such as inflammatory mediators and macrophages. Mycophenolic acid, administered to the rats having undergone balloon injury, was used as an experimental tool in the study. ^ Neointimal formation was observed 14 days after balloon injury to the carotid artery. Intimal areas and intimal/medial area (I/M) ratios were significantly decreased in rats treated with MPA compared to those treated with vehicle. The immunohistochemical analysis of α-actin indicated that most of cells in the neointimal layer were SMCs. The number of Proliferating Cell Nuclear Antigen (PCNA) positive SMCs was significantly decreased whereas the PCNA positive cell ratio was increased in rats treated with MPA compared to those treated with vehicle. These data indicate the arresting of SMCs in the S phase of the cell cycle by MPA. Thymidine incorporation and washout assays confirmed the direct inhibitory effect of MPA on SMC proliferation. Therefore, SMC proliferation may play a major role in neointimal growth. ^ In addition, this research examines the association of inflammatory mediators, such as intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS) with neointimal growth. Treatment of rats with MPA as compared to rats treated with vehicle inhibited MCP-1 and iNOS expression with no apparent change in ICAM-1 expression. The inhibitory effects of MPA on MCP-1 and iNOS expression were also confirmed by in vitro studies. ^ Since cytokines and growth factors released from macrophages may stimulate the expression of inflammatory mediators or stimulate SMC proliferation, the inhibition of macrophages by MPA may contribute to its inhibitory effects on neointimal growth. By examining these interrelationships between inflammation and proliferation, this work contributes to the understanding of the pathogenesis of restenosis, thereby provides valuable information for potential approaches to reduce the rate of restenosis. ^