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(Hypertension. 2006;48:671.)
© 2006 American Heart Association, Inc.

Original Articles

Attenuation of Inflammatory Vascular Remodeling by Angiotensin II Type 1 Receptor–Associated Protein

Akira Oshita; Masaru Iwai; Rui Chen; Ayumi Ide; Midori Okumura; Shiori Fukunaga; Toyofumi Yoshii; Masaki Mogi; Jitsuo Higaki; Masatsugu Horiuchi

From the Department of Molecular and Cellular Biology (A.O., M.I., R.C., A.I., M.O., S.F., M.M., M.H.), Division of Medical Biochemistry and Cardiovascular Biology, and Second Department of Internal Medicine (A.O., T.Y., J.H.), Ehime University School of Medicine, Tohon, Ehime, Japan.

Correspondence to Masatsugu Horiuchi, Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

	Abstract

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To explore the role of angiotensin II Type 1 receptor–associated protein (ATRAP) in vascular remodeling, we developed transgenic mice for mouse ATRAP cDNA and examined remodeling after inflammatory vascular injury induced by polyethylene cuff placement. In ATRAP transgenic (ATRAP-Tg) mice, ATRAP mRNA was increased 3- to 4-fold in the heart, aorta, and femoral artery. ATRAP-Tg mice showed no significant change in body weight, systolic blood pressure, heart rate, and heart/body weight ratio. However, cell proliferation and neointimal formation in the injured artery were attenuated in ATRAP-Tg mice. The increase in NADPH oxidase activity and the expression of p22^phox, a reduced nicotinamide-adenine dinucleotide/reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit, after cuff placement was also attenuated in ATRAP-Tg mice. Moreover, activation of extracellular signal–regulated kinase, signal transducer and activator of transcription 1, and signal transducer and activator of transcription 3 after cuff placement was significantly reduced in ATRAP-Tg mice. Pressor response and cardiac hypertrophy induced by angiotensin II infusion and pressure overload were also attenuated in ATRAP-Tg mice. These results suggest that ATRAP plays an important role in vascular remodeling as a negative regulator.

Key Words: receptors, angiotensin II • signal transduction • vascular diseases • muscle, smooth, vascular

	Introduction

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The cardiovascular actions of angiotensin II (Ang II) are mainly mediated by the Ang II type 1 (AT₁) receptor. Previous reports indicate that the intracellular carboxyl-terminal tail of the receptor plays an important role in activation of receptor-coupled G protein and internalization of the AT₁ receptor.^1–6 We cloned a novel AT₁ receptor-associated protein (ATRAP) using a yeast 2-hybrid screening system.⁷ ATRAP has 3 transmembrane domains and interacts with the intracellular carboxyl-terminal domain of the AT₁ receptor, but it does not interact with the AT₂ receptor, m₃ muscarinic receptor, bradykinin B₂ receptor, endothelin ETB receptor, or ß₂-adrenergic receptor. It is reported that ATRAP modulates AT₁ receptor function in COS-7 cells, human embryonic kidney 293 cells, and cultured mouse cardiomyocytes. Overexpression of ATRAP significantly decreases the number of AT₁ receptors on the cell surface and also decreases the degree of p38 mitogen-activated protein kinase phosphorylation, activity of the c-fos promoter, and protein synthesis on Ang II treatment.^7–9 We also reported that overexpression of ATRAP in cultured vascular smooth muscle cells (VSMCs) enhanced internalization of the AT₁ receptor and attenuated DNA synthesis and activation of extracellular signal-regulated kinase (ERK), Akt, and signal transducer and activator of transcription (STAT) induced by Ang II.¹⁰

Polyethylene cuff placement around the femoral artery induces inflammatory vascular injury and remodeling responses accompanied by an increase in AT₁ and AT₂ receptor expression. VSMC proliferation, neointimal formation, inflammatory response, and oxidative stress in vascular injury were significantly attenuated in AT₁ a receptor-deficient mice.^11–13 Moreover, administration of an AT₁ receptor blocker, valsartan, also decreased vascular remodeling. These results strongly suggest that ATRAP may act as an important regulator of VSMC proliferation and vascular remodeling. In the present study, we prepared transgenic mice for ATRAP and examined its role in inflammatory vascular injury induced by polyethylene cuff placement around the femoral artery.

	Methods

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Transgene Constructs and Screening of Transgenic Mice
The hybrid cytomegalovirus enhancer/chicken ß-actin (CAG) promoter and a mouse ATRAP cDNA were subcloned into the plasmid pCAG-GS. The plasmid containing the CAG promoter and ATRAP cDNA was microinjected into the pronuclei of fertilized mouse embryos at the single-cell stage to generate transgenic mice (C57BL/6 strain). Transgenic mice were identified by PCR using 5'-ATGGAGCTGCCTGCCGTGAA-3' as the forward primer and 5'-GTTCACGGTGCATGTGGTAG-3' as the reverse primer.

Cuff Placement
Adult male ATRAP transgenic (ATRAP-Tg) mice (10 to 12 weeks of age) and wild-type mice (C57BL/6J) were used in this study. The mice were housed in a room in which lighting was controlled (12 hours on and 12 hours off), and room temperature was kept at 25°C. They were given a standard diet (MF, Oriental Yeast Co, Ltd) and water ad libitum. The experimental protocol was approved by the Animal Studies Committee of Ehime University. Inflammatory vascular injury was induced by polyethylene cuff placement around the femoral artery under anesthesia with intraperitoneal injection of ketamine (70 mg/kg) and xylazine (4 mg/kg) according to methods described previously,^11–14 and morphometric analysis to measure neointimal area was performed as described previously.^11–13 The heart/body weight ratio was calculated as whole heart weight (milligrams) divided by body weight (grams). Blood pressure and heart rate were measured under consciousness by the indirect tail- cuff method with a blood pressure monitor (MK-1030, Muromachi Kikai Co, Ltd). The mice were held in a case where temperature was kept at 37°C.

Infusion of Ang II and Aortic Banding
Ang II was infused intraperitoneally at a dose of 1 µg/kg per minute for 2 weeks using an osmotic minipump. The aortic banding was performed under anesthesia with intraperitoneal injection of ketamine (70 mg/kg) and xylazine (4 mg/kg) according to the method described previously.^15,16 After 4 weeks, the hearts were excised, weighed, and heart/body weight ratio was expressed as heart weight (milligrams) versus body weight (grams) as described previously.^15,16

Immunohistochemical Staining
Rabbit polyclonal antibody against the epitope mapped at the C-terminus of ATRAP (CPFASLENKGQAAPRG) was prepared by the Peptide Institute, Inc. Anti-p22^phox antibody was purchased from Santa Cruz Biotechnology Inc.¹³ Formalin-fixed, paraffin-embedded sections were prepared using femoral artery at 7 days after cuff placement. Proliferating cell nuclear antigen (PCNA) was stained with anti-PCNA antibody (Novocastra Laboratories, Ltd.) using an M.O.M. immunodetection kit (Vector Laboratories, Inc).^11,13 ATRAP and p22^phox were stained using biotin-labeled secondary antibodies and Cy3-labeled streptavidin as described previously.^11,12 Paraffin-embedded sections were incubated with anti-p22^phox and ATRAP antibody, washed, and incubated with biotin-labeled secondary antibodies, then incubated with Cy3-labeled streptavidin. Serial sections treated with secondary antibodies alone did not show specific staining. Samples were examined with a Zeiss Axioskop microscope equipped with a computer-based imaging system.¹³

Western Blot Analysis
Total proteins were prepared from pooled arteries (n=3, each pool contained 4 arteries from 4 mice) at 7 days after cuff placement. Phosphorylation of ERK, STAT1, and STAT3 was detected by Western blot using specific antibodies as described previously.^13,17

NADPH Oxidase Activity
A tissue protein sample was prepared from the femoral artery at 7 days after cuff placement by homogenization in 500 µL of ice-cold Tris-sucrose buffer. Reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity was quantified by cytochrome c method from the absorbance with or without superoxide dismutase, as described previously.^18,19

Real-Time RT-PCR
Total RNA was extracted from the femoral arteries (n=3, each pool contained 4 arteries from 4 mice). Real-time quantitative RT-PCR was performed with Premix Ex Taq (Takara Bio Inc). PCR primers for ATRAP were the same as for genotyping; for the AT₁ receptor they were 5'-GTTCCTGCTCACGTGTCTCA-3' (forward) and 5'-CATCAGCCAGATGATGATGC-3' (reverse); for the AT₂ receptor they were 5'-CCTGCATGAGTGTCGATAGGT-3' (forward) and 5'-CCAGCAGACCACTGAGCATA-3' (reverse); and for GAPDH they were 5'-ATGTAGGCCATGAGGTCCAC-3' (forward) and 5'-TGCGACTTCAACAGCAACTC-3' (reverse).

Statistical Analysis
The data were analyzed by 1-way ANOVA. If a statistically significant effect was found, post hoc analysis by Bonferroni’s test was performed to detect the difference between the groups. A value of P<0.05 was considered statistically significant.

	Results

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Expression of ATRAP in Injured Artery After Cuff Placement in Wild-Type Mice
Expression of ATRAP in the femoral artery was examined by real-time RT-PCR and immunohistochemical staining. Figure 1A shows immunostaining of ATRAP in the femoral artery at 7 days after cuff placement or sham operation. ATRAP was observed mainly in the media of the intact artery. ATRAP was transiently decreased in the media at 7 days after cuff placement. This decrease in ATRAP after cuff placement was accompanied by a decrease in mRNA (Figure 1B). The decrease in ATRAP protein and mRNA had recovered by 14 days after cuff placement.

View larger version (15K): [in this window] [in a new window]   Figure 1. Expression of ATRAP in injured femoral artery after cuff placement in WT mice. Cuff placement around the femoral artery was performed as described in the Methods section, and artery samples were obtained after cuff placement. Immunostaining and real-time quantitative RT-PCR analysis for ATRAP were performed as described in the Methods section. A, Representative result of immunohistochemical staining for ATRAP in femoral artery. Top, without cuff placement; bottom, 7 days after cuff placement. B, Change in ATRAP mRNA expression in femoral artery. Values are standardized against GAPDH mRNA level. Values are mean±SE (n=6 to 8 for each group). *P<0.05 vs without cuff.

Blood Pressure, Heart Rate, Heart/Body Ratio, and ATRAP Expression in ATRAP-Tg Mice
Three founder lines that transmitted the transgene were established by Southern blot (ATRAP-Tg 10, 11, and 15). Because ATRAP-Tg 15 showed the highest expression of ATRAP mRNA (Figure I, available online at http://hyper. ahajournals.org), heterozygous animals of this line were used in the present study. Body size, body weight, and behavior of ATRAP-Tg mice were not different from those of C57BL/6J (wild-type [WT]) mice. As shown in the Table, systolic blood pressure, heart rate, and heart/body weight ratio in ATRAP-Tg mice were not significantly different from those in WT mice. ATRAP expression increased 3- to 4-fold in the heart, aorta, and femoral artery of ATRAP-Tg mice (Figure II). Media/lumen ratio of the intact femoral artery in ATRAP-Tg mice also did not differ from that in WT mice (Figure IIIA). Expression of the AT₁ receptor in the heart, aorta, and femoral artery was not significantly different between WT and ATRAP-Tg mice (Figure III B).

View this table: [in this window] [in a new window]   Systolic Blood Pressure, Heart Rate, and Heart Weight/Body Weight Ratio

Effect of ATRAP on VSMC Proliferation and Neointimal Formation After Cuff Placement in ATRAP-Tg Mice
Cuff placement induces proliferation of VSMC and neointimal formation in the femoral artery.^12,14,20 Figure 2 shows PCNA labeling index in the media and intima at 7 days after cuff placement in WT and ATRAP-Tg mice. The control (noninjured) levels of PCNA index were not significantly different between WT and ATRAP-Tg groups. However, the increase in PCNA index in the injured artery was suppressed in ATRAP-Tg mice. Related to the change in PCNA index, neointimal formation at 14 days after cuff placement was also attenuated in ATRAP-Tg mice (Figure 3).

View larger version (29K): [in this window] [in a new window]   Figure 2. Cell proliferation in injured femoral artery after cuff placement in ATRAP-Tg mice. Cuff placement around the femoral artery was performed, and PCNA was detected as described in the Methods section. Cell proliferation was measured as the ratio of PCNA-positive nuclei to total nuclei in the femoral artery at 7 days after cuff placement. Values are mean±SE (n=6 to 8 for each group). *P<0.05 vs WT.

View larger version (34K): [in this window] [in a new window]   Figure 3. Neointimal formation in injured femoral artery after cuff placement in ATRAP-Tg mice. Cuff placement around the femoral artery and morphometric measurement were performed as described in the Methods section. Areas of media and neointima in the femoral artery were measured at 14 days after cuff placement in cross-sections after elastica van Gieson staining. Values are mean±SE (n=6 to 8 for each group).

Inhibition of Oxidative Stress After Cuff Placement in ATRAP-Tg Mice
The increase in in situ superoxide production in the injured artery at 7 days after cuff placement was significantly attenuated in ATRAP-Tg mice. It is reported that superoxide production is mainly mediated by NADPH oxidase.^13,21,22 NADPH oxidase activity in the injured artery was lowered in ATRAP-Tg mice (Figure 4A). Moreover, expression of p22^phox, a membrane-associated reduced nicotinamide-adenine dinucleotide/NADPH oxidase subunit, was also attenuated in ATRAP-Tg mice (Figure 4B).

View larger version (16K): [in this window] [in a new window]   Figure 4. NADPH oxidase activity and expression of p22phox in injured artery after cuff placement in ATRAP-Tg mice. Cuff placement around the femoral artery was performed, and protein samples were prepared at 7 days after cuff placement as described in the Methods section. NADPH oxidase activity was measured, and immunostaining was performed as described in the Methods section. A, NADPH oxidase activity in femoral arteries after cuff placement. B, Representative results of immunohistochemical staining of p22phox from 5 independent experiments (top) and measurement of fluorescence (bottom). Values are mean±SE (n=6 to 8 for each group). *P<0.05 vs without cuff.

Change in Intracellular Signaling in the Injured Artery of ATRAP-Tg Mice
As reported previously, cuff placement increases phosphorylation of ERK, STAT1, and STAT3 via AT₁ receptor stimulation.^17,23 The phosphorylation level of these markers was not significantly different between WT and ATRAP-Tg mice (Figure 5). However, the increase in phosphorylation of these markers after cuff placement was suppressed in ATRAP-Tg mice.

View larger version (30K): [in this window] [in a new window]   Figure 5. Phosphorylation of ERK, STAT1, and STAT3 in injured femoral artery after cuff placement in ATRAP-Tg mice. Tissue samples were prepared from arteries 7 days after cuff placement, and signaling molecules were detected as described in the Methods section. Top, Representative results of Western blot for phosphorylated and total ERK, STAT1, and STAT3 using 3 different pooled samples. Bottom, Densitometric analysis of Western blots. Values are mean±SE. *P<0.05 vs without cuff. p indicates phospho.

Effect of ATRAP on Cardiac Hypertrophy
The degree of cardiomyocyte hypertrophy was evaluated by calculating the ratio of heart weight/body weight. This parameter did not differ between WT and ATRAP-Tg mice before aortic banding (Figure 6). Heart-to-body weight ratio was increased 4 weeks after aortic banding in both mice strains, whereas these parameters were smaller in ATRAP-Tg mice (Figure 6A). Administration of Ang II, at 1 µg/kg per minute for 14 days, increased heart/body weight ratio with the increase in systolic blood pressure, whereas increases in these parameters were less in ATRAP-Tg mice (Figure 6B and 6C).

View larger version (15K): [in this window] [in a new window]   Figure 6. Effect of ATRAP overexpression on the response to Ang II infusion and aortic banding. Ang II (1 µg/kg per minute) was administered intraperitoneally for 14 days using osmotic minipump. Aortic banding was performed as described in the Methods section. Measurement of blood pressure and heart/body weight ratio were performed as described in the Methods section. A, Heart/body weight ratio 4 weeks after aortic banding. B, Systolic blood pressure induced by intraperitoneal infusion of Ang II. , WT mice; •, ATRAP-Tg mice. C, Heart/body weight ratio after Ang II administration for 14 days. Values are mean±SE (n=5 to 8 for each group). *P<0.05 vs without aortic banding or Ang II. P<0.05 vs WT without aortic banding (A) or Ang II infusion (C).

	Discussion

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In the present study, we demonstrated that VSMC proliferation, neointimal formation, and inflammatory response in the injured artery after cuff placement were inhibited in ATRAP-Tg mice compared with those in WT mice. The AT₁ receptor is a 7 trans-membrane receptor distributed in most adult tissues and mediates the major action of Ang II. The intracellular carboxy-terminal of the AT₁ receptor is capable of binding with intracellular signaling molecules like PLC-1, SHP-2, and Jak2.^3,4 ATRAP is a novel protein associated with the intracellular carboxy-terminal domain.⁷ Previous reports suggest that ATRAP accelerates internalization of the AT₁ receptor and attenuates the AT₁ receptor-mediated response.^8–10 Functional analysis of the effects of ATRAP on Ang II-induced AT₁ receptor signaling revealed decreases in the generation of inositol lipids, Ang II–stimulated transcriptional activity of the c-fos promoter and STAT, and cell proliferation. A recent study showed that ATRAP interacts with calcium-modulating cyclophilin ligand and decreases Ang II– or calcium-modulating cyclophilin ligand-induced nuclear factor of activated T cell transcriptional activation.²⁴ We reported that overexpression of ATRAP increased internalization of the AT₁ receptor in cultured VSMCs. In these cells, an increase in thymidine incorporation and in ERK phosphorylation induced by Ang II was attenuated. These results indicate that ATRAP suppresses AT₁ receptor–mediated signaling by stimulating internalization of the receptor. On the other hand, Ang II is involved in vascular remodeling through stimulation of the AT₁ receptor. Using an animal model of inflammatory vascular injury induced by polyethylene-cuff placement around the femoral artery, we demonstrated that VSMC proliferation, neointimal formation, and inflammatory response were markedly suppressed by blockade of AT₁ receptor–mediated signaling with an ARB or AT₁ receptor gene knockout.^11,12,17,23 Because the overexpression of ATRAP suppresses AT₁ receptor–mediated signaling, it is suggested that the increased ATRAP activity may inhibit vascular remodeling. In fact, ATRAP expression was decreased in the injured artery at 7 days after cuff placement in WT mice, when neointimal formation and inflammation were not yet obvious (Figure 1A and 1B). Therefore, it is possible that change in ATRAP level may affect remodeling of the injured artery.

To examine the function of ATRAP in an in vivo injury model, we developed ATRAP-Tg mice. Expression of ATRAP mRNA in the heart, aorta, and femoral artery in these mice was 3- to 4-fold higher than in WT mice (Figure II). However, ATRAP-Tg mice showed no significant change in growth, body weight, heart rate, blood pressure, and heart/body weight ratio (Table). These results indicate that overexpression of ATRAP did not affect basal physiological markers. Expression of AT₁ receptor mRNA was not significantly changed in the heart, aorta, and femoral artery of ATRAP-Tg mice. The effect of ATRAP on internalization of the AT₁ receptor may appear only when the AT₁ receptor is stimulated by Ang II.

ATRAP-Tg mice showed a decrease in vascular remodeling induced by cuff placement (Figure 1A and 1B). Because AT₁ receptor stimulation increases inflammation, VSMC proliferation, and oxidative stress,^21,25 the results in ATRAP-Tg mice suggest that overexpression of ATRAP inhibits AT₁ receptor–mediated responses in vascular injury. We have performed additional studies to examine whether the overexpression of ATRAP could also reduce cardiac hypertrophy related to Ang II and observed that cardiac hypertrophy induced by pressure overload or Ang II infusion and pressor response induced by Ang II infusion were attenuated in ATRAP-Tg mice. These results suggest that overexpression of ATRAP attenuates the cardiac hypertrophy mediated mainly by AT₁ receptor stimulation, although it is also possible that the inhibition of cardiac hypertrophy in ATRAP-Tg mice may also be caused by the reduced pressor response, because myocardial hypertrophy can be because of elevated blood pressure, and overexpression of ATRAP attenuated the pressor response to Ang II infusion in our study.

In our vascular injury model, oxidative stress, such as superoxide production and NADPH oxidase activity, was increased after cuff placement.¹³ This increase in oxidative stress was also suppressed in ATRAP-Tg mice (Figure 4). Moreover, phosphorylation of intracellular signaling molecules like ERK, STAT1, and STAT3, which are stimulated through the AT₁ receptor, was attenuated in the injured artery of ATRAP-Tg mice (Figure 5).

Perspectives
Our results suggest that an increase in ATRAP expression in vivo attenuates AT₁ receptor–mediated signaling and thereby reduces vascular remodeling. There could be the possibility that increase in expression of ATRAP could be having effects in the intact animal other than AT₁ receptor inhibition. However, the detailed mechanisms of the function of ATRAP, for example, the regulation of ATRAP expression, possible ligands for ATRAP, and the regulatory mechanism of the action of ATRAP on phosphorylation and/or dephosphorylation of signaling molecules need to be clarified. The results of the present study suggest that ATRAP may be a novel drug target for the treatment of pathological vascular remodeling.

	Acknowledgments

 
Sources of Funding

This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan; the Cardiovascular Research Foundation; the Mitsubishi Pharma Research Foundation; Takeda Science Foundation; and the Novartis Foundation of Gerontological Research.

Disclosures

None.

Received May 16, 2006; first decision June 20, 2006; accepted July 18, 2006.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Klein U, Ramirez MT, Kobilka BK, von Zastrow M. A novel interaction between adrenergic receptors and the alpha-subunit of eukaryotic initiation factor 2B. J Biol Chem. 1997; 272: 19099–19102.[Abstract/Free Full Text]
2. Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ. The beta2-adrenergic receptor interacts with the Na⁺/H⁺-exchanger regulatory factor to control Na⁺/H⁺ exchange. Nature (Lond). 1998; 392: 626–630.[CrossRef][Medline] [Order article via Infotrieve]
3. Ali MS, Sayeski PP, Dirksen LB, Hayzer DJ, Marrero MB, Bernstein KE. Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT₁ receptor. J Biol Chem. 1997; 272: 23382–23388.[Abstract/Free Full Text]
4. Venema RC, Ju H, Venema VJ, Schieffer B, Harp JB, Ling BN, Eaton DC, Marrero MB. Angiotensin II-induced association of phospholipase C1 with the G-protein-coupled AT₁ receptor. J Biol Chem. 1998; 273: 7703–7708.[Abstract/Free Full Text]
5. Tang H, Guo DF, Porter JP, Wanaka Y, Inagami T. Role of cytoplasmic tail of the type 1A angiotensin II receptor in agonist- and phorbol ester-induced desensitization. Circ Res. 1998; 82: 523–531.[Abstract/Free Full Text]
6. Thomas WG, Thekkumkara TJ, Motel TJ, Baker KM. Stable expression of a truncated AT₁ a receptor in CHO-K1 cells. The carboxyl-terminal region directs agonist-induced internalization but not receptor signaling or desensitization. J Biol Chem. 1995; 270: 207–213.[Abstract/Free Full Text]
7. Daviet L, Lehtonen JY, Tamura K, Griese DP, Horiuchi M, Dzau VJ. Cloning and characterization of ATRAP, a novel protein that interacts with the angiotensin II type 1 receptor. J Biol Chem. 1999; 274: 17058–17062.[Abstract/Free Full Text]
8. Lopez-Ilasaca M, Liu X, Tamura K, Dzau VJ. The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin II signaling. Mol Biol Cell. 2003; 14: 5038–5050.[Abstract/Free Full Text]
9. Tanaka Y, Tamura K, Koide Y, Sakai M, Tsurumi Y, Noda Y, Umemura M, Ishigami T, Uchino K, Kimura K, Horiuchi M, Umemura S. The novel angiotensin II type 1 receptor (AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy. FEBS Lett. 2005; 579: 1579–1586.[CrossRef][Medline] [Order article via Infotrieve]
10. Cui T, Nakagami H, Iwai M, Takeda Y, Shiuchi T, Tamura K, Daviet L, Horiuchi M. ATRAP, novel AT₁ receptor associated protein, enhances internalization of AT₁ receptor and inhibits vascular smooth muscle cell growth. Biochem Biophys Res Commun. 2000; 279: 938–941.[CrossRef][Medline] [Order article via Infotrieve]
11. Suzuki J, Iwai M, Nakagami H, Wu L, Chen R, Sugaya T, Hamada M, Hiwada K, Horiuchi M. Role of angiotensin II-regulated apoptosis through distinct AT₁ and AT₂ receptors in neointimal formation. Circulation. 2002; 106: 847–853.[Abstract/Free Full Text]
12. Chen R, Iwai M, Wu L, Suzuki J, Min LJ, Shiuchi T, Sugaya T, Liu HW, Cui TX, Horiuchi M. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension. 2003; 42: 542–547.[Abstract/Free Full Text]
13. Jinno T, Iwai M, Li Z, Li JM, Liu HW, Cui TX, Rakugi H, Ogihara T, Horiuchi M. Calcium channel blocker azelnidipine enhances vascular protective effects of AT₁ receptor blocker olmesartan. Hypertension. 2004; 43: 263–269.[Abstract/Free Full Text]
14. Akishita M, Horiuchi M, Yamada H, Zhang L, Shirakami G, Tamura K, Ouchi Y, Dzau VJ. Inflammation influences vascular remodeling through AT₂ receptor expression and signaling. Physiol Genomics. 2000; 2: 13–20.[Abstract/Free Full Text]
15. Akishita M, Iwai M, Wu L, Zhang L, Ouchi Y, Dzau VJ, Horiuchi M. Inhibitory effect of AT₂ receptor on coronary arterial remodeling after aortic banding in mice. Circulation. 2000; 102: 1684–1689.[Abstract/Free Full Text]
16. Wu L, Iwai M, Nakagami H, Chen R, Suzuki J, Akishita M, de Gasparo M, Horiuchi M. Effect of AT₁ receptor blockade on cardiac remodeling in AT₂ receptor null mice. Arteriosclero Thromb Vascular Biol. 2002; 22: 49–54.
17. Horiuchi M, Cui TX, Li Z, Li JM, Nakagami H, Iwai M. Fluvastatin enhances the inhibitory effects of a selective angiotensin II type 1 receptor blocker, valsartan, on vascular neointimal formation. Circulation. 2003; 107: 106–112.[Abstract/Free Full Text]
18. Szocs K, Lassegue B, Sorescu D, Hilenski LL, Valppu L, Couse TL, Wilcox JN, Quinn MT, Lambeth JD, Griendling KK. Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury. Arterioscler Thromb Vasc Biol. 2002; 22: 21–27.[Abstract/Free Full Text]
19. Kolbeck RC, She ZW, Callahan LA, Nosek TM. Increased superoxide production during fatigue in the perfused rat diaphragm. Am J Respir Crit Care Med. 1997; 156: 140–145.[Abstract/Free Full Text]
20. Akishita M, Ouchi Y, Miyoshi H, Kozaki K, Inoue S, Ishikawa M, Eto M, Toba K, Orimo H. Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells. Atherosclerosis. 1997; 130: 1–10.[CrossRef][Medline] [Order article via Infotrieve]
21. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74: 1141–1148.[Abstract/Free Full Text]
22. Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK. p22^phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem. 1996; 271: 23317–23321.[Abstract/Free Full Text]
23. Liu HW, Iwai M, Takeda-Matsubara Y, Wu L, Li JM, Okumura M, Cui TX, Horiuchi M. Effect of estrogen and AT₁ receptor blocker on neointima formation. Hypertension. 2002; 40: 451–457.[Abstract/Free Full Text]
24. Guo S, Lopez-Ilasaca M, Dzau VJ. Identification of calcium-modulating cyclophilin ligand (CAML) as transducer of angiotensin II-mediated nuclear factor of activated T cells (NFAT) activation. J Biol Chem. 2005; 280: 12536–12541.[Abstract/Free Full Text]
25. Dzau VJ. Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension. 2001; 37: 1047–1052.[Abstract/Free Full Text]

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