A potent activator of PPARalpha and gamma 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 PPARalpha and gamma, on the vascular cell recruitment. TNF-alpha- or interleukin-1beta (IL-1beta)-induced THP-1 cell attachment to cultured endothelial cells was significantly reduced in the presence of 10 microM 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 microM 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 PPARalpha and gamma activator inhibits the recruitment of macrophages and SMCs in intima, possibly leading to the reduction of intimal hyperplasia in hypercholesterolemia.