(Hypertension. 1998;31:45.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Increased Cardiac Angiotensin II Receptors in Angiotensinogen-Deficient Mice
From the Second Department of Internal Medicine, Yokohama City University School of Medicine (Y.S., S.U., K.T., M.K., S.K., T.I., M.Y., N.N., H.O., M.I.), Yokohama, and the Institute of Applied Biochemistry (A.F., K.M.) and the Gene Experiment Center (H.M.), University of Tsukuba, Ibaraki, Japan.
Correspondence to Satoshi Umemura, MD, Second Department of Internal Medicine, Yokohama City University School of Medicine, 3–9, Fukuura, Kanazawa-ku, Yokohama 236, Japan.
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Abstract |
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Abstract—Two subtypes of angiotensin II (Ang II) receptors, type 1 (AT1-R) and type 2 (AT2-R), have been identified in the heart. However, little is known about the regulation of cardiac AT1-R and AT2-R by Ang II in vivo. Thus, we examined cardiac AT1-R and AT2-R in angiotensinogen-deficient (Atg-/-) mice that are hypotensive and lack circulating Ang II. Cardiac Ang II receptors (Ang II-R) were assessed by radioligand binding with 125I-[Sar1,Ile8]–Ang II in plasma membrane fractions. AT1-R and AT2-R were distinguished using their specific antagonists CV-11974 and PD123319, respectively. Total densities of Ang II-R and AT1-R density were significantly greater in the Atg-/- mice than Atg+/+ mice (31.1±2.8 versus18.8±2.1, 28.7±3.0 versus16.9±2.3 fmol/mg protein, P<.01, respectively), and AT2-R showed a slight but not significant increase in Atg-/- mice relative to Atg+/+ control animals. Kd values were not different between the two groups. In contrast to binding experiments, levels of Ang II type 1a receptor (AT1a-R) and AT2-R mRNA did not differ between Atg-/- and Atg+/+ mice. These results suggest that lack of Ang II may upregulate AT1-R through translational and/or posttranslational mechanisms in Atg-/- mice.
Key Words: angiotensin II • receptors, angiotensin II • angiotensinogen • mice
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Introduction |
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The RAS plays an important role in the control of cardiovascular homeostasis.1 2 Several studies have indicated the existence of local RAS in the heart.3 4 5 6 The major biologically active product of the RAS is the multifunctional peptide Ang II. Ang II exerts its biological effects via binding to its specific receptors located on the plasma membrane.7 Ang II-R are separated into at least two subtypes, AT1-R and AT2-R. Dup753 and CV11974 inhibit AT1-R, which is the predominant subtype in the adrenal cortex,8 vasculature,9 kidney,10 and liver,11 whereas PD123319 and CGP42112A inhibit AT2-R, which is present primarily in the adrenal medulla,8 uterus,9 ovary,12 brain,13 and the developing fetus.14 AT1-R was shown to mediate all the biological effects traditionally ascribed to Ang II, such as vasoconstriction, aldosterone release, facilitation of adrenergic outflow, cellular proliferation, and growth.8 9 15 16
AT2-R is expressed in fetal tissue, most conspicuously mesenchymal tissues14 and specific brain nuclei of the rat.17 Expression of AT2-R decreases rapidly after birth. These results indicated developmental, neurological, and reproductive roles of Ang II via AT2-R. Recently, Ichiki et al18 and Hein et al19 found that the AT2-R is involved in the maintenance of systemic blood pressure and responsiveness of the cardiovascular system to Ang II. In addition, it was shown that AT2-R contributes to induction of apoptosis20 and voltage-sensitive ion currents.21
To further study the roles of RAS in the maintenance of cardiovascular homeostasis, angiotensinogen-deficient (Atg-/-) mice were generated by gene targeting.22 The Atg-/- mice, lacking the functional RAS, clearly exhibited chronic hypotension with systolic blood pressure reduced by 33.5 mm Hg relative to the wild-type Atg+/+ control animals.22 This result indicated an indispensable role of RAS in maintenance of blood pressure.
On the other hand, the recently generated Tsukuba hypertensive mice, transgenic mice harboring the human genes for renin and angiotensinogen,23 show hypertension and cardiac hypertrophy. In this model, Ang II is overexpressed and cardiac Ang II-R were reported to be upregulated at both protein and mRNA levels.24
However, little is known about the regulation of cardiac AT1-R and AT2-R in Atg-/- mice, which have no Ang II. Therefore, this study was designed to determine whether cardiac AT1-R and AT2-R are altered in Atg-/- mice as compared with Atg+/+ mice.
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Methods |
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Animals
Atg+/+ (n=14) and Atg-/- (n=14) mice, aged 8 weeks, were used. Homozygous mutant mice were generated by gene targeting as described previously.22 The mice were housed two to three animals per cage and maintained under controlled conditions of light, temperature, and humidity. All animals had free access to tap water and rat chow with 0.3% NaCl purchased from Oriental Kobo Kogyo. At 10 weeks of age, systolic blood pressure was measured in 10 mice in each group, and body weight was measured in all mice in each group. Systolic blood pressure was measured by tail-cuff plethysmography as previously described.23 After killing the mice at 10 weeks of age by decapitation, the hearts were rapidly excised, washed in cold saline, and weighed. The hearts were frozen in liquid nitrogen and stored at -80°C.
Radioligand Binding Assay
Membrane Preparation
As the hearts of mice are very small, we used two hearts for one
radioligand binding assay. The whole hearts were minced in
an ice-cold buffer containing 0.32 mol/L sucrose, 10 mmol/L
Tris-HCl, 2 mmol/L EDTA (pH, 8.0), 3 mmol/L
MgCl2,, 1 mmol/L phenylmethylsulfonyl
fluoride (PMSF), 8 µg/mL antipain, 16 µg/mL leupeptin (pH
7.4 at 4°C), and homogenized using a Brinkman Polytron
(Kinematica) with three 10-second bursts at a setting of 8. The
homogenate was centrifuged at 550g for
10 minutes at 4°C. The supernatant was centrifuged at
50 000g for 10 minutes at 4°C. The pellet was resuspended
in an ice-cold 10 mmol/L Tris-HCl buffer containing 3 mmol/L
MgCl2, 1 mmol/L EGTA, 1 mmol/L PMSF, 8
µg/mL antipain, 16 µg/mL leupeptin, and recentrifuged.
The final pellet was resuspended in a buffer of 10 mmol/L Tris-HCl buffer containing 3 mmol/L MgCl2, 1 mmol/L EGTA, 1 mmol/L PMSF, 8 µg/mL antipain, 16 µg/mL leupeptin, and immediately used for radioligand receptor binding experiments.
Radioligand Receptor Binding Assay
125I-[Sar,1Ile8]–Ang
II binding to membrane fractions was assayed as previously
reported.24 The incubation mixtures contained a
suspension of membranes (approximately 140 to 300 µg of protein), 70
pmol/L
125I-[Sar,1Ile8]–Ang
II, incubation buffer, and Ang II antagonist
(Sar,1Ile8-Ang II,
CV-11974, PD123319) at various concentrations (10 pmol/L to 10
µmol/L), in a final volume of 200 µL. Incubation was carried out
for 120 minutes at 25°C and was terminated by rapid filtration
through a 0.3% polyethylenimine-treated Whatman GF/C glass fiber
filter. The filter was washed three times with 4 mL of ice-cold washing
buffer containing 10 mmol/L Tris-HCl, 1 mmol/L EGTA, 3
mmol/L MgCl2, and 2 mg/mL bovine serum
albumin.
The radioactivity trapped on the filters was quantified with an automatic gamma counter (Beckman Gamma 5500). Nonspecific binding of 125I-[Sar,1Ile8]–Ang II was defined as the radioactivity that bound to membrane fractions and was not displaced by a high concentration of unlabeled Sar,1Ile8-Ang II (1 µmol/L). Specific 125I-[Sar,1Ile8]–Ang II binding displaced by CV-11974 and PD123319 was estimated as AT1-R and AT2-R, respectively. Each binding assay was carried out in duplicate. Protein concentration of the membrane suspension was determined by the method of Lowry et al.25 Maximum binding capacity (Bmax), dissociation constant (Kd), and results of competition studies were analyzed with the LIGAND computer program.
Northern Blot Hybridization
RNA Isolation and Analysis
We focused on the expression levels of cardiac
AT1a-R and AT2-R mRNA in
Atg-/- and Atg+/+ mice, because it has been
reported that the subtype of AT1-R that is
expressed in the mouse heart is exclusively
AT1a-R.26 Northern blot
analysis was performed essentially as described
previously.27 Total RNA from tissues was
extracted using the guanidinum isothiocyanate–cesium chloride
centrifugation method.28 RNA
samples (30 µg) were denatured with 1 mol/L glyoxal and 50%
dimethlsulfoxide, electrophoresed on 1.2% agarose gels, and
transferred onto nylon membranes (GeneScreen Plus, DuPont–New England
Nuclear). Filters were prehybridized for 30 minutes at 60°C in a
solution consisting of 1% SDS, 1 mol/L NaCl, and 10% dextran sulfate.
Hybridization proceeded for 18 hours at 65°C in the same solution
containing 200 µg/mL denatured salmon sperm DNA and
1x106 cpm/mL of the
32 P-labeled cDNA probes for mouse
AT1a-R, AT2-R, or
18S-ribosomal RNA.29 The 490-bp
SacI/PmaCI fragment that corresponds to
3'-untranslated regions of AT1a-R was used as the
AT1a-R–specific probe as previously
described.27 The 1020-bp
HindIII/XbaI fragment of
AT2-R DNA was used as the
AT2-R probe.30 Since the
sequence homology between AT1a-R and
AT2-R cDNAs was approximately
50%,30 31 the probes used for quantification of
AT1a-R should not cross-react with
AT2-R transcripts and vice versa under our
experimental condition of stringency. Filters were washed twice with
2xSSC (1xSSC containing 0.15 mol/L NaCl and 0.015 mol/L sodium
citrate) for 5 minutes at room temperature, twice with 0.1xSSC for 15
minutes at room temperature. Dried filters were exposed to the imaging
plate of a FUJIX BAS2000 BIO-Imaging Analyzer (Fuji Photo
Film).
Statistical Analysis
All data are presented as mean±SE. Statistical
analysis was performed by Student’s t test.
Statistical significance was accepted at the level of
P<.05.
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Results |
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The systolic blood pressure and the ratio of heart weight to body weight were significantly decreased in Atg-/- mice (Table 1).
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Radioligand Binding Assay
The binding of
125I-[Sar,1Ile8]–Ang
II to Atg+/+ heart membranes was saturable and maximal
binding was observed within 120 minutes after commencement of
incubation (Fig 1).The
t1/2 of association was 31 minutes (Fig 1).
Scatchard analysis revealed the presence of a single
high-affinity binding site in both groups (Fig 2). Nonspecific binding was 
30% of
the total binding at Kd.
Bmax of Ang II-R and
AT1-R were significantly increased in
Atg-/- mice compared with Atg+/+ control animals,
although Kd was not different between the
two groups (Fig 2, Table 2).
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To characterize the two subtypes of Ang II-R in Atg+/+ and Atg-/- mice, competition binding experiments were carried out using their respective antagonists. Replacement of the labeled antagonist 125I-[Sar,1Ile8]–Ang II by Sar,1Ile8–Ang II, CV- 11974, and PD123319 in mouse heart membranes is shown in Fig 3.
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About 90% of the binding sites were blocked by 1 µmol/L CV11974 and were therefore classified as AT1-R. Conversely, about 10% of specific binding sites were blocked by 1 µmol/L PD123319 and were regarded as AT2-R. The proportions of AT1-R and AT2-R were not different between the groups (Table 2).
Cardiac Expression of AT1-R and AT2-R mRNA
in Atg+/+ and Atg-/- Mice
We next examined whether the expression of
AT1-R and AT2-R mRNAs was
modulated by null mutation of angiotensinogen gene. As
shown in Fig 4A, the
AT1a-R probes did not cross-react with
AT2-R transcripts. Northern blot analysis
of heart RNA from Atg+/+ and Atg-/- mice revealed
similar levels of AT1a-R and
AT2-R mRNAs between the two groups (Fig 4A and 4B).
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Discussion |
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The present study was designed to examine the effects of Ang II deficiency on the density and affinity of the cardiac Ang II-R, as well as the levels of AT1-R and AT2-R mRNA. Total density of cardiac Ang II-R as well as AT1-R density were greater in Atg-/- than Atg+/+ mice, whereas levels of AT1a-R and AT2-R mRNA were not different between the two groups. Although there are two subtypes of AT1-R in the mouse tissues, AT1a-R and AT1b-R, it has been reported that the subtype of AT1-R that is expressed in the mouse heart is exclusively AT1a-R.26 Therefore, the results described above indicate that cardiac AT1-R may be upregulated by Ang II deficiency through translational and/or posttranslational mechanisms in Atg-/- mice.
The regulation of AT1-R by Ang II has been studied in several tissues,32 33 34 and the results have suggested tissue-specific changes. For example, AT1-R mRNA was increased in the liver and decreased in the kidney after salt depletion.32 Infusion of Ang II induced upregulation of AT1-R mRNA levels in the adrenal gland but not in the kidney, aorta, or brainstem.33
Changes of cardiac AT1-R have been also studied under several conditions, especially in cardiac hypertrophy. However the results are controversial. The pressure overload was reported to induce upregulation of AT1-R and AT1-R mRNA levels,5 while another study showed the downregulation of AT1-R.35 In the hypertrophic heart induced by volume overload, no significant increase in AT1-R mRNA was observed.36 The regulation and the pathological roles of Ang II-R in cardiac hypertrophy may be different depending on the experimental model used, possibly due to the mechanisms of overload that are present in the heart (such as pressure overload and volume overload), degree of fibrosis, activity of RAS, and the contributions of other hypertrophic stimuli such as the endothelin system,37 38 cytokine system,39 and sympathetic nervous system activity.40
A recent in vitro study showed that AT1-R mRNA and AT2-R mRNA in myocytes were upregulated by mechanical stretching via Ang II–independent mechanisms, although Ang II secreted from stretched myocytes might downregulate AT1-R mRNA and AT2-R mRNA.41
In our study, the ratio of heart weight to body weight of Atg-/- mice was smaller than that in Atg+/+ mice. Thus, the mechanisms by which the hypertrophic heart is regulated might not involve in the increase of AT1-R in Atg-/- mice.
Many G protein–coupled receptors such as ß2-adrenergic receptors are upregulated or downregulated if the ligand concentrations are decreased or increased, respectively. In these cases, internalization of the receptors is induced through phosphorylation. In some cases, regulation of the expression of these receptors at the mRNA level is also involved.42
The results of studies of the regulation of cardiac AT1-R by the ligand Ang II are not consistent. The decrease in plasma Ang II that was induced by administration of the ACE inhibitor ramipril did not affect cardiac AT1-R mRNA,43 but administration of AT1 antagonists was reported to upregulate44 or downregulate34 AT1-R mRNA in the heart. The increase in plasma Ang II that was induced by the subcutaneous infusion of frusemide did not affect cardiac AT1-R mRNA expression,43 but in renovascular hypertension this treatment was reported to upregulate5 as well as downregulate AT1-R mRNA expression.43
Although in an in vitro study Kijima et al showed the downregulation of myocyte AT1-R mRNA that was induced by Ang II,41 the results of in vivo studies are still controversial as described above, perhaps due to the involvement of more complicated regulatory systems other than Ang II. For example, a recent report suggested that Ang II-R, especially AT1a-R, were predominantly expressed in cardiac fibroblasts instead of in myocytes in the rat heart.45 Thus, the ratio of distributions of cardiac fibroblasts and myocytes may be also important factors that determine the AT1-R levels in vivo.
In contrast to these reports, our experimental system was relatively simple because Atg-/- mice are completely deficient of Ang II. In fact we could not detect any circulating Ang II in Atg-/- mice by our preliminary experiment. This system clearly showed that AT1-R is upregulated as a result of Ang II deficiency. Since AT1-R mRNA level was not different between Atg-/- and Atg+/+ mice, the increase in AT1-R in Atg-/- mice may have been due to the translational and/or posttranslational mechanisms. Since compensatory mechanisms (such as the sympathetic nervous–catecholamine system and vasopressin system) may be activated in Atg-/- mice to compensate for the decrease in blood pressure,46 these systems may also be involved in the modulation of AT1-R mRNA expression in the heart.
In the present study, we could not find any difference in the density of AT2-R expression or AT2-R mRNA level between Atg-/- and Atg+/+ mice. Because signal mechanisms and biological functions of AT2-R remain to be determined47 48 and because AT2-R is expressed at a low level as compared with AT1-R in the heart, the regulation of AT2-R by Ang II has remained unclear.
Interestingly, the discrepancies between changes in AT1-R protein and mRNA levels evoked by Ang II were also reported in the kidney. Sechi et al reported that Ang II infusion had no effect on AT1-R mRNA level but that it downregulated Ang II receptor density through a posttranscriptional mechanism.32
In conclusion, the present study showed that AT1-R was increased in Atg-/- mice relative to wild-type control animals, but that AT1-R mRNA level was similar between the two groups, suggesting that cardiac AT1-R may be upregulated through translational and/or posttranslational mechanisms in Atg-/- mice.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank Takeda Chemical Industries, Ltd (Osaka, Japan) for supplying CV11974 and Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company (USA) for supplying PD123319. The probe for AT1a-R was kindly provided by Dr Takeshi Sugaya, Lead Generation Research Laboratories, Tanabe Seiyaku Co, Ltd (Osaka, Japan).
Received March 17, 1997; first decision April 14, 1997; accepted August 28, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Robertson JIS, Nicholls MG, eds. The Renin-Angiotensin System. London, England: Gower Medical Publishing; 1993.
2. Garrison JC, Peach MJ. Renin and angiotensin. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The Pharmacological Basis of Therapeutics. Elmsford, NY: Pergamon Press, Inc; 1990:749–763.
3. Dostal DE, Rothblum KN, Chernin MI, Cooper GR, Baker KM. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in neonatal rat heart. Am J Physiol. 1992;263:C838–C850.[Medline] [Order article via Infotrieve]
4. Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy: effects on coronary resistance, contractility, and relaxation. J Clin Invest. 1990;86:1913–1920.[Medline] [Order article via Infotrieve]
5. Suzuki J, Matsubara H, Urakami M, Inada M. Rat
angiotensin II (type 1A) receptor mRNA regulation and
subtype expression in myocardial growth and hypertrophy.
Circ Res. 1993;73:439–447.
6. Matsubara H, Kanasaki M, Murasawa S, Tsukaguchi Y, Nio Y, Inada M. Differential gene expression and regulation of angiotensin II receptor subtypes in rat cardiac fibroblasts and cardiomyocytes in culture. J Clin Invest. 1994;93:1592–1601.[Medline] [Order article via Infotrieve]
7. Peach MJ. Renin-angiotensin system:
biochemistry and mechanisms of action. Physiol Rev. 1977;57:313–370.
8. Chiu AT, Herblin WF, McCall DE, Ardecky RJ, Carini DJ, Duncia JV, Pease LJ, Wong PC, Wexler RR, Johnson AL, Timmermans PBMWM. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989;165:196–203.[Medline] [Order article via Infotrieve]
9. Whitebread S, Mele M, Kamber B, de Gasparo M. Preliminary biochemical characterization of two angiotenisin II receptor subtypes. Biochem Biophys Res Commun. 1989;163:284–291.[Medline] [Order article via Infotrieve]
10. Sechi LA, Grady EF, Griffin CA, Kalinyak JE, Schambelan M. Distribution of angiotensin II receptor subtypes in rat and human kidney. Am J Physiol. 1992;262:F236–F240.[Medline] [Order article via Infotrieve]
11. Speth RC, Kim KH. Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II, p-aminophenylalanine6 angiotensin II. Biochem Biophys Res Commun. 1990;169:997–1006.[Medline] [Order article via Infotrieve]
12. Pucell AG, Hodges JC, Sen I, Bumpus FM, Husain A.
Biochemical properties of the ovarian granulosa cell type
2-angiotensin II receptor. Endocrinology. 1991;128:1947–1959.
13. Chang RSL, Lotti VJ, Chen TB, Faust KA. Two angiotensin II binding sites in rat brain revealed using [125I]Sar,1 Ile8-angiotensin II and selective nonpeptide antagonists. Biochem Biophys Res Commun. 1990;171:813–817.[Medline] [Order article via Infotrieve]
14. Grady EF, Sechi LA, Griffin CA, Schambelam M, Kalinyak JE. Expression of AT2 receptors in the developing rat fetus. J Clin Invest. 1991;88:921–933.[Medline] [Order article via Infotrieve]
15. Bottari SP, de Gasparo M, Steckelings UM, Levens NR. Angiotensin II receptor subtypes: characterization, signalling mechanisms, and possible physiological implications. Front Neuroendocrinol. 1993;14:123–171.[Medline] [Order article via Infotrieve]
16. Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993;45:205–251.[Medline] [Order article via Infotrieve]
17. Tsutsumi K, Viswanathan M, Strömberg C, Saavedra JM. Type-1 and type-2 angiotensin II receptors in fatal rat brain. Eur J Pharmacol. 1991;198:89–92.[Medline] [Order article via Infotrieve]
18. Ichiki T, Labosky PA, Shiota C, Okuyama S, Inagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BLM, Inagami T. Effects on blood pressure and exploratory behavior of mice lacking angiotensin II type-2 receptor. Nature. 1995;377:748–750.[Medline] [Order article via Infotrieve]
19. Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor gene in mice. Nature. 1995;377:744–747.[Medline] [Order article via Infotrieve]
20. Yamada T, Horiuchi M, Dzau VJ. Angiotensin
II type 2 receptor mediates programmed cell death. Proc Natl Acad
Sci U S A. 1996;93:156–160.
21. Kang J, Sumners C, Posner P. Angiotensin II type 2 receptor-modulated changes in potassium currents in cultured neurons. Am J Physiol. 1993;265:C607–C616.[Medline] [Order article via Infotrieve]
22. Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E,
Yagami K, Fukamizu A, Murakami K. Angiotensinogen-deficient
mice with hypotension. J Biol Chem. 1994;269:31334–31337.
23. Fukamizu A, Sugimura K, Takimoto E, Sugiyama F, Seo MS,
Takahashi S, Hatae T, Kajiwara N, Yagami K, Murakami K. Chimeric
renin-angiotensin system demonstrates sustained increase in
blood pressure of transgenic mice carrying both human renin and human
angiotensinogen genes. J Biol Chem. 1993;268:11617–11621.
24. Fujii N, Tanaka M, Ohnishi J, Yukawa K, Takimoto E, Shimada S, Naruse M, Sugiyama F, Yagami K, Murakami K, Miyazaki H. Alterations of angiotensin II receptor contents in hypertrophied hearts. Biochem Biophys Res Commun. 1995;212:326–333.[Medline] [Order article via Infotrieve]
25. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein
measurement with the folin phenol reagent. J Biol Chem. 1951;193:265–275.
26. Burson JM, Aguilera G, Gross KW, Sigmund CD. Differential expression of angiotensin receptor 1A and 1B in mouse. Am J Physiol. 1994;267:E260–E267.[Medline] [Order article via Infotrieve]
27. Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E,
Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Uchida
H, Sugiura M, Fukuta K, Fukamizu A, Murakami K. Angiotensin
II type 1a receptor-deficient mice with hypotension and hyperreninemia.
J Biol Chem. 1995;270:18719–18722.
28. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–159.[Medline] [Order article via Infotrieve]
29. Raynal F, Michot B, Bachellerie JP. Complete nucleotide sequence of mouse 18S rRNA gene: comparison with other available homologs. FEBS Lett. 1984;167:263–268.[Medline] [Order article via Infotrieve]
30. Kobayashi S, Ohnishi J, Nibu Y, Nishimatsu S, Umemura S, Ishii M, Murakami K, Miyazaki H. Cloning of the rat angiotensin II type 2 receptor gene and identification of its functional promotor region. Biochem Biophys Acta. 1995;1262:155–158.[Medline] [Order article via Infotrieve]
31. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991;351:233–236.[Medline] [Order article via Infotrieve]
32. Sechi LA, Griffin CA, Giacchetti G, Valentin JP,
Llorens-Cortes C, Corvol P, Schambelan M. Tissue-specific regualtion of
type 1 angiotensin II receptor mRNA levels in the rat.
Hypertension. 1996;28:403–408.
33. Iwai N, Inagami T. Regulation of the expression of the rat angiotensin II receptor mRNA. Biochem Biophys Res Commun. 1992;182:1094–1099.[Medline] [Order article via Infotrieve]
34. Kitami Y, Okura T, Marumoto K, Wakamiya R, Hiwada K. Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat. Biochem Biophys Res Commun. 1992;188:446–452.[Medline] [Order article via Infotrieve]
35. Lopez JJ, Lorell BH, Ingelfinger JR, Weinberg EO, Schunkert H, Diamant D, Tang S-S. Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts. Am J Physiol. 1994;267:H844–H852.[Medline] [Order article via Infotrieve]
36. Iwai N, Shimoike H, Kinoshita M. Cardiac
renin-angiotensin system in the hypertrophied heart.
Circulation. 1995;92:2690–2696.
37. Fareh J, Touyz RM, Schiffrin EL, Thibault G.
Endothelin-1 and angiotensin II receptors in cells from
hypertrophied heart. Circ Res. 1996;78:302–311.
38. Arai M, Yoguchi A, Iso T, Takahashi T, Imai S, Murata K, Suzuki T. Endothelin-1 and its binding sites are upregulated in pressure overload cardiac hypertrophy. Am J Physiol. 1995;268:H2084–H2091.[Medline] [Order article via Infotrieve]
39. Kunisada K, Hirota H, Fujio Y, Matsui H, Tani Y,
Yamauchi-Takihara K, Kushimoto T. Activation of JAK-STAT and MAP
kinases by leukemia inhibitory factor through gp130 in
cardiac myocytes. Circulation. 1996;94:2626–2632.
40. Simpson P. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha1 adrenergic response. J Clin Invest. 1983;72:732–738.[Medline] [Order article via Infotrieve]
41. Kijima K, Matsubara H, Murasawa S, Maruyama K, Mori Y,
Ohkubo N, Komuro I, Yazaki Y, Iwasaka T, Inada M. Mechanical stretch
induces enhanced expression of angiotensin II receptor
subtypes in neonatal rat cardiac myocytes. Circ Res. 1996;79:887–897.
42. Hein L, Kobilka BK. Adrenergic receptor signal transduction and regulation. Neuropharmacology. 1995;34:357–266.[Medline] [Order article via Infotrieve]
43. Bruna RD, Ries S, Himmelstoss C, Kurtz A. Expression of cardiac angiotensin II AT1 receptor genes in rat hearts is regulated by steroids but not by angiotensin II. J Hypertens. 1995;13:763–769.[Medline] [Order article via Infotrieve]
44. Everett AD, Tufro-McReddie A, Fisher A, Gomez RA.
Angiotensin receptor regulates cardiac
hypertrophy and transforming growth
factor-ß1 expression. Hypertension. 1994;23:587–592.
45. Matsubara H, Kanasaki M, Murasawa S, Tsukaguchi Y, Nio Y, Inada M. Differential gene expression and regulation of angiotensin II receptor subtypes in rat cardiac fibroblasts and cardiomyocytes in culture. J Clin Invest. 1994;93:1592–1601.[Medline] [Order article via Infotrieve]
46. Umemura S, Kihara M, Sumida Y, Yabana M, Ishigami T, Tamura K, Nyui N, Hibi K, Murakami K, Fukamizu A, Ishii M. Endocrinological abnormalities in angiotensinogen-gene knockout mice: studies of hormonal responses to dietary salt loading. J Hypertens. In press.
47. Webb ML, Liu EC-K, Cohen RB, Hedberg A, Bogosian EA, Monshizadegan H, Molloy C, Serafino R, Moreland S, Murphy TJ, Dickinson KEJ. Molecular characterization of angiotensin II type II receptors in rat pheochromocytoma cells. Peptides. 1992;13:499–508.[Medline] [Order article via Infotrieve]
48. Takahashi K, Bardhan S, Kambayashi Y, Shirai H, Inagami T. Protein tyrosine phosphatase inhibition by angiotensin II in rat pheochromocytoma cells through type 2 receptor, AT2. Biochem Biophys Res Commun. 1994;198:60–66.[Medline] [Order article via Infotrieve]
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