818 ACTIVATION OF ANG II TYPE 1 RECEPTOR-ASSOCIATED PROTEIN SUPPRESSES VASCULAR HYPERTROPHY AND OXIDATIVE STRESS IN ANG II-MEDIATED HYPERTENSION

Abstract

Objective: We cloned a novel molecule interacting with Ang II type 1 receptor, which we named ATRAP (for Ang II type 1 receptor-associated protein). The present study was designed to investigate the putative functional role of ATRAP in vascular hypertrophy and oxidative stress in Ang II-mediated hypertension in vivo. Methods & Results: We generated transgenic (Tg) mice expressing ATRAP in tissues including aorta under control of the β-actin promoter. The mRNA levels of ATRAP in Tg mice aorta were increased 15-fold compared with C57BL/6J Wild-type (Wt) mice. Adult male Wt mice and Tg mice at from 10 to 12 weeks of ages, were divided into two groups for the subcutaneous infusion of vehicle or Ang II 500ng/kg/min via osmotic mini-pump for 14days. Although systolic blood pressure was significantly elevated in the Ang II-infused mice, there was no significant difference in systolic blood pressure of Ang II-infused Tg mice compared to that of Ang II-infused Wild type mice. In Wt mice, the Ang II treatment promoted vascular hypertrophy in aorta, concomitant with a significant increase in aortic NADPH oxidase component, p22phox, expression. On the other hand, in ATRAP transgenic mice, the development of vascular hypertrophy and activation of p22phox in the context of Ang II treatment were significantly suppressed. Conclusions: These results demonstrate that activation of ATRAP at local tissue sites including aorta efficiently inhibits the vascular hypertrophy and oxidative stress provoked in Ang II-mediated hypertension, thereby suggesting ATRAP to be a novel therapeutic target in vascular disease.