Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator‐Activated Receptor‐ γ : Therapeutic Implications for Cardiovascular Diseases

Abstract

Proliferation of vascular smooth muscle cells (SMCs) is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator‐activated receptor (PPAR) γ is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD), used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPAR γ is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPAR γ in SMCs are genes encoding proteins involved in the regulation of cell‐cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof‐of‐concept clinical studies. This review will summarize the transcriptional target genes regulated by PPAR γ in SMCs and outline the therapeutic implications of PPAR γ activation for the treatment and prevention of atherosclerosis and its complications.