title: Activation of angiotensin II type 1 receptor-associated protein exerts an inhibitory effect on vascular hypertrophy and oxidative stress in angiotensin II-mediated hypertension.
abstract: OBJECTIVE
  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 renin-angiotensin system. In this study, we investigated the effects of ATRAP on Ang II-induced vascular remodelling.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wakui
authors.forename: Toru
authors.initials: T
authors.lastname: Dejima
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Kazushi
authors.initials: K
authors.lastname: Uneda
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.forename: Akinobu
authors.initials: A
authors.lastname: Maeda
authors.forename: Masato
authors.initials: M
authors.lastname: Ohsawa
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kanaoka
authors.forename: Kengo
authors.initials: K
authors.lastname: Azushima
authors.forename: Ryu
authors.initials: R
authors.lastname: Kobayashi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003573:Cytochrome b Group / Q000378:metabolism; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D000447:Aldehydes; D003573:Cytochrome b Group; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C515614:Cyba protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal
keywords: Angiotensin receptor; Atherosclerosis; Hypertrophy; Oxidative stress; Vascular smooth muscle cells