Angiotensin II Type 2 Receptor Inhibits Vascular Intimal Proliferation With Activation of PPARγ

Angiotensin II type 2 (AT(2)) receptor stimulation could exert beneficial effects on vascular remodeling. Previously, we reported that AT(2) receptor stimulation ameliorated insulin resistance in diabetic mice accompanied by PPAR gamma activation which also plays a variety of crucial roles in the vasculature. Therefore, this study aimed to investigate the vascular protective effect of the AT(2) receptor with activation of PPAR gamma involving AT(2) receptor-interacting protein (ATIP). Vascular injury was induced by polyethylene-cuff placement around the femoral artery in C57BL/6J mice. Treatment with compound 21 (C21), an AT(2) receptor agonist, decreased neointimal formation, cell proliferation, and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-alpha, and interleukin-1 beta, and phosphorylation of nuclear factor-kappa B, and increased PPAR gamma DNA-binding activity in the injured artery, whereas these inhibitory effects of C21 were attenuated by co-treatment with a PPAR gamma antagonist, GW9662. Treatment of vascular smooth muscle cells (VSMC) with C21 prepared from smAT(2) transgenic mice, which highly express the AT(2) receptor in VSMC, increased both PPAR gamma activity and its DNA-binding activity determined by dual-luciferase assay and electrophoresis mobility shift assay (EMSA), respectively. We observed that ATIP was involved in PPAR gamma complex formation, and that transfection of siRNA of ATIP1 attenuated the AT(2) receptor-mediated increase in PPAR gamma activity in VSMC. In response to AT(2) receptor stimulation, ATIP was translocated from the plasma membrane to the nucleus. Our results suggest a new mechanism by which AT(2) receptor stimulation activates PPAR gamma, thereby resulting in amelioration of vascular intimal proliferation, and that ATIP plays an important role in AT(2) receptor-mediated PPAR gamma activation.