Attenuation of Cuff-Induced Neointimal Formation by Overexpression of Angiotensin II Type 2 Receptor-Interacting Protein 1

Abstract

Recently we have cloned angiotensin II type 2 receptor–interacting protein 1 (ATIP1) as a novel protein that interacts specifically with the C-terminal tail of the angiotensin II type 2 receptor; however, the pathophysiological roles of ATIP1 in vascular remodeling are still unknown. Here, we generated ATIP1-transgenic (ATIP1-Tg) mice expressing mouse ATIP1 and investigated the role of ATIP1 in vascular remodeling using these transgenic mice. ATIP1-Tg mice exhibited no significant difference in blood pressure compared with wild-type (WT) mice. Angiotensin II type 2 receptor mRNA expression in the femoral artery was increased in injured femoral arteries, reaching a peak at 7 days after operation in WT mice, and a similar result of angiotensin II type 2 receptor expression was observed in ATIP1-Tg mice. In ATIP1-Tg mice, neointimal formation of the femoral artery 14 days after cuff placement was significantly smaller than that in WT mice. 5-Bromo-2′-deoxyuridine incorporation was significantly reduced in the injured arteries of ATIP1-Tg mice compared with WT mice. In ATIP1-Tg mice, superoxide anion production and the expression of a proinflammatory cytokine, tumor necrosis factor-α, were markedly attenuated. Moreover, cell proliferative signaling, such as extracellular signal-regulated kinase phosphorylation, was significantly attenuated in ATIP1-Tg mice compared with WT mice. Taken together, these results suggest that ATIP1 plays an important role in cuff-induced vascular remodeling in mice.