A potent activator of PPARα and γ reduces the vascular cell recruitment and inhibits the intimal thickning in hypercholesterolemic rabbits

Peroxisome proliferator-activated receptors (PPARs) regulate the vascular cell functions as well as systemic lipid and glucose metabolism. Here, we studied the effect of TAK-559, a newly developed potent activator both for PPARα and γ, on the vascular cell recruitment. TNF-α - or interleukin-1β (IL-1β)-induced THP-1 cell attachment to cultured endothelial cells was significantly reduced in the presence of 10 μM TAK-559 (P< 0.05). The secretion of monocyte chemoattractant protein-1 (MCP-1) from endothelial cells is reduced by 36% in the presence of 10 μM TAK-559, accompanied with the decreased mRNA expression in the cells. The proliferation and migration of cultured smooth muscle cells (SMCs) were significantly decreased in the presence of TAK-559 (P< 0.05). TAK-559-treated hypercholesterolemic rabbits showed the significant reduction of intimal thickning after balloon catheterization by 51% compared with control (P< 0.05), although the plasma lipid and glucose level was not changed between them. The numbers of macrophage and SMCs were decreased to 34% and 49% in the hyperplastic intima of arteries from TAK-559-treated rabbits compared to those from control, respectively. These results suggest that the PPARα and γ activator inhibits the recruitment of macrophages and SMCs in intima, possibly leading to the reduction of intimal hyperplasia in hypercholesterolemia.