Cardiac-specific activation of angiotensin II type 1 receptor-associated protein completely suppresses cardiac hypertrophy in chronic angiotensin II-infused mice.
We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor-associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II-mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy by angiotensin II infusion in vivo. We first examined the effect of angiotensin II infusion on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy, concomitant with a significant decrease in cardiac ATRAP expression, but without significant change in cardiac angiotensin II type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the alpha-myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy, activation of p38 mitogen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin II treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice. These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy.
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Hiromichi
H
Wakui
Kouichi
K
Tamura
Yutaka
Y
Tanaka
Miyuki
M
Matsuda
Yunzhe
Y
Bai
Toru
T
Dejima
Shin-Ichiro
S
Masuda
Atsu-Ichiro
A
Shigenaga
Akinobu
A
Maeda
Masaki
M
Mogi
Naoaki
N
Ichihara
Yusuke
Y
Kobayashi
Nobuhito
N
Hirawa
Tomoaki
T
Ishigami
Yoshiyuki
Y
Toya
Machiko
M
Yabana
Masatsugu
M
Horiuchi
Susumu
S
Minamisawa
Satoshi
S
Umemura
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000627:therapeutic use; D000804:Angiotensin II / Q000009:adverse effects*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000627:therapeutic use
D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D012313:RNA; C437965:olmesartan; D020929:Mitogen-Activated Protein Kinase Kinases