Activation of angiotensin II type 1 receptor-associated protein exerts an inhibitory effect on vascular hypertrophy and oxidative stress in angiotensin II-mediated hypertension

作者：Wakui Hiromichi; Dejima Toru; Tamura Kouichi^*; Uneda Kazushi; Azuma Koichi; Maeda Akinobu; Ohsawa Masato; Kanaoka Tomohiko; Azushima Kengo; Kobayashi Ryu; Matsuda Miyuki; Yamashita Akio; Umemura Satoshi

来源：Cardiovascular Research, 2013, 100(3): 511-519.

DOI：10.1093/cvr/cvt225

• Angiotensin receptor
• Atherosclerosis
• Hypertrophy
• Oxidative stress
• Vascular smooth muscle cells

Activation of tissue angiotensin II (Ang II) type 1 receptor (AT1R) plays an important role in the development of vascular remodelling. We have shown that the AT1R-associated protein (ATRAP/Agtrap), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent pathological activation of the tissue reninangiotensin system. In this study, we investigated the effects of ATRAP on Ang II-induced vascular remodelling. %26lt;br%26gt;Transgenic (Tg) mice with a pattern of aortic vascular-dominant overexpression of ATRAP were obtained, and Ang II or vehicle was continuously infused into Tg and wild-type (Wt) mice via an osmotic minipump for 14 days. Although blood pressure of Ang II-infused Tg mice was comparable with that of Ang II-infused Wt mice, the Ang II-mediated development of aortic vascular hypertrophy was partially inhibited in Tg mice compared with Wt mice. In addition, Ang II-mediated up-regulation of vascular Nox4 and p22(phox), NADPH oxidase components, and 4-HNE, a marker of reactive oxygen species (ROS) generation, was significantly suppressed in Tg mice, with a concomitant inhibition of activation of aortic vascular p38MAPK and JNK by Ang II. This protection afforded by vascular ATRAP against Ang II-induced activation of NADPH oxidase is supported by in vitro experimental data using adenoviral transfer of recombinant ATRAP. %26lt;br%26gt;These results indicate that activation of aortic vascular ATRAP partially inhibits the Nox4/p22(phox)-ROS-p38MAPK/JNK pathway and pathological aortic hypertrophy provoked by Ang II-mediated hypertension, thereby suggesting ATRAP as a novel receptor-binding modulator of vascular pathophysiology.

• 出版日期2013-12-1