(Hypertension. 1997;29:1044-1050.)
© 1997 American Heart Association, Inc.
Articles |
Induction of Renin in Medial Smooth Muscle Cells by Balloon Injury
From the 1st Department of Internal Medicine, Shiga University of Medical Sciences, Ohtsu City, Japan, and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenn (T.I.).
Correspondence to Naoharu Iwai, MD, 1st Department of Internal Medicine, Shiga University of Medical Sciences, Tsukinowa Seta, Ohtsu-city 520-21, Shiga-ken, Japan. E-mail iwai{at}suncuore.shiga-med.ac.jp
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Abstract |
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Abstract We studied the expression of each component of the renin-angiotensin system (renin, angiotensin I–converting enzyme, angiotensinogen, and angiotensin II type I receptor) in balloon-injured rat carotid artery. We assessed the expression levels of the respective mRNAs by competitive polymerase chain reaction. Renin mRNA concentration was markedly increased 24 hours after balloon injury and remained higher than that in the control at 7 days after balloon injury. Angiotensin-converting enzyme mRNA concentration was decreased 24 hours after balloon injury and was increased at 14 days after balloon injury. No significant change in angiotensinogen mRNA concentration was observed throughout the study period. Angiotensin type I receptor mRNA concentration was increased beginning 3 days after balloon injury and remained higher than that in the control at 14 days after balloon injury. Immunohistochemical analysis showed that renin was transiently expressed in medial smooth muscle cells after balloon injury. Administration of quinapril markedly reduced neointimal formation and was accompanied by an attenuation of the increase in the concentrations of angiotensin type I receptor and angiotensin-converting enzyme mRNAs. The upregulation of renin mRNA in balloon-injured rat carotid artery preceded and may play a role in neointimal formation.
Key Words: renin • intima • balloon injury
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Introduction |
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The best-studied model of neointimal formation is the response of the rat carotid artery to balloon injury.1 2 In the rat, the balloon-injury model begins with complete destruction of the endothelium and extensive death of medial smooth muscle cells, followed by medial smooth muscle cell proliferation.3 4 Medial smooth muscle cells migrate into the intima2 5 6 and then start a transient burst phase of proliferation.7 Finally, smooth muscle cells deposit large amounts of extracellular matrix material.8
Many kinds of growth factors and cytokines, such as basic fibroblast growth factor, Ang II, platelet-derived growth factors, insulin-like growth factor I, and transforming growth factor-ß, have been suggested to play important roles in neointimal formation following balloon injury. Blockade of the RAS by ACE inhibitors or AT1R antagonists has been shown to reduce neointimal formation in the rat.5 9 10 Ang II is known to be a growth-promoting factor.11 Several previous studies have indicated that Ang II generation might be elevated in balloon-injured artery. Induction of both ACE gene expression in neointima12 13 and AGT gene expression in the media and neointima14 have been reported. Smooth muscle cells in the neointima have been reported to show a higher expression level of AT1R than those in the media.15 This increased AT1R expression in neointimal smooth muscle cells may in itself be sufficient to enhance the local proliferation of smooth muscle cells caused by Ang II.
However, the increased expression of ACE, AGT, and AT1R were all observed 1 week after balloon injury and did not seem to precede neointimal formation. Recent detailed analyses of the mechanisms of ACE inhibitors in reducing neointimal formation have indicated that the inhibition of smooth muscle cell migration from media to intima is the main mechanism by which neointimal formation is reduced.16 17 The migration of smooth muscle cells from media to intima reportedly occurs 3 to 14 days after balloon injury.2 17 If Ang II is responsible for this migration, enhanced generation of or sensitivity to Ang II should occur before this migration. Therefore, we investigated the time course of the expression of renin, ACE, AGT, and AT1R mRNAs in balloon-injured rat carotid artery.
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Methods |
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Carotid Artery Balloon Injury
Male Sprague-Dawley rats (350 to 400 g) were obtained from Clea Japan (Osaka). The rats were anesthetized with sodium pentobarbital (40 mg/kg IP). A 2F Fogarty catheter (Baxter) was inserted through the right iliac artery to the left common carotid artery. The left common carotid artery was exposed for visual confirmation of catheter insertion. The inflated balloon (0.4 mL air) was pulled through the common carotid artery three times, and the right iliac artery was permanently ligated. This study was conducted in accordance with current guidelines for the care and use of experimental animals of Shiga University of Medical Sciences.
RNA Isolation and Analysis
Rats were perfused via the left ventricle with ice-cold
phosphate-buffered saline (PBS: 150 mmol/L NaCl in 10 mmol/L
Na2HPO4/NaH2PO4, pH
7.4) to remove blood, and the left and right common carotid arteries
between the bifurcation of the external carotid artery and aorta were
carefully removed. A small portion (5 mm) was cut from the aortic
end. For RNA isolation, the adventitia was carefully removed, and
three carotid arteries were pooled to make one RNA sample. Total RNA
was extracted according to the method of Chomczynski and
Sacchi18 with a polytron homogenizer
(Kinematica AG). RNA concentration was spectrophotometrically
determined at 260 nm, and RNA quality was visually confirmed by agarose
gel electrophoresis, as previously reported.19 The
expression levels of renin, ACE, AGT, and AT1R mRNAs were
determined by a competitive RT-PCR method as previously
reported.19 20 21
Briefly, 2 µg of total RNA samples mixed with known amounts
(Table
) of the deletion- or insertion-mutated cRNA for
renin, ACE, AGT, and AT1R underwent RT using random
primers. The resulting cDNA mixture was purified by phenol/chloroform
extraction and two rounds of ethanol precipitation with ammonium
acetate and dissolved in 40 µL water. Five microliters of the cDNA
mixture was amplified in a total reaction mixture of 25 µL containing
50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 1.5 to 2.0
mmol/L MgCl2, 0.01% (wt/vol) gelatin, 0.2 mmol/L
dNTP, 50 nmol/L [
-32P]dCTP (3000 Ci/mmol), 25 pmol of
sense and antisense primers, and 0.5 U Taq DNA polymerase
(Toyobo). The PCR amplification profile included an initial denaturing
step at 94°C for 1 minute and 30 to 35 cycles at 94°C for 1 minute,
58°C for 1 minute, and 74°C for 1 to 2 minutes. The PCR
products were electrophoresed on a 1.7% agarose gel for visual
inspection and a 5% polyacrylamide gel for precise
quantification, as previously reported.19 20 21 The primers
and sizes of the PCR products are summarized in the Table. Since
the mutated cRNA for ACE has a 4-bp insertion at the Avr II
site, the PCR product from the mutated cRNA lacks this
Avr II site. The PCR product from native ACE mRNA should
liberate 195- and 122-bp fragments by Avr II (New England
Biolabs, Inc) digestion. More than 90% of the AT1R mRNA
expressed in the control and balloon-injured arteries was
AT1aR mRNA (data not shown). Expression levels of the mRNAs
were calculated as Expression Level (molecules per microgram)=Amount of
Mutated cRNA
(molecules)x(IN/IM)x(CM/CN),
where IN and IM represent the intensity
of the PCR product from native and mutated RNAs, respectively, and
CN and CM represent the content of dCTP
in the PCR product from native and mutated RNA, respectively.
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To confirm whether the PCR products correspond to the native mRNA, the PCR products were directly sequenced by a sequencing kit (Taq Cycle sequencing kit, Takara Shyuzo, Co Ltd).
Immunohistochemistry
The rats were deeply anesthetized with sodium
pentobarbital (70 mg/kg IP). They were then perfused via the left
ventricle, initially with ice-cold PBS (150 mmol/L NaCl in 10
mmol Na2HPO4/NaH2PO4,
pH 7.4) and subsequently with a fixative containing 4%
paraformaldehyde in 0.1 mol/L phosphate buffer (0.1
mol/L Na2HPO4/NaH2PO4,
pH 7.4). The carotid arteries were immersed for 2 days in a
postfixative containing 4% paraformaldehyde in
phosphate buffer at 4°C. The arteries were then placed in phosphate
buffer containing 15% sucrose for 2 days. The arteries were frozen and
cut into 20-µm-thick sections with a cryostat. The sections were
rinsed for at least 2 days with several changes of PBS containing 0.3%
Triton X-100 (PBST) at 4°C before immunohistochemical
staining.
Free-floating sections, which were pretreated with 0.5% H2O2 in PBST to destroy intrinsic peroxidase activity, were incubated for 2 days at 4°C with rabbit anti-rat renin antiserum (diluted 1:60 000), for 1 hour at room temperature with biotinylated anti-rabbit IgG (diluted 1:1000), and for 1 hour at room temperature with avidin-biotin-peroxidase complex (diluted 1:4000, ABC Elite, Vector). All sera were diluted with PBST, and sections were always rinsed in PBST after each step. Peroxidase activity was revealed by 0.02% 3,3'-diaminobenzidine (Wakenyaku) in 50 mmol/L Tris-HCl (pH 7.6), 0.005% H2O2, and 0.3% nickel ammonium sulfate. Control experiments included the substitution of primary antiserum with preimmune serum or preabsorbed serum, which showed no specific staining. Rabbit antiserum to rat renin was prepared as previously reported.22 Its specificity was ascertained by the lack of a cross-reaction with human renin and rat cathepsin D, at dilutions greater than 1:500. Used at a dilution of 1:80 000 in the immunohistochemical staining of rat kidney by the method described above, juxtaglomerular cells were stained exclusively.
Effects of Quinapril
Quinapril was dissolved in drinking water. Quinapril (10 mg/kg
per day) or placebo (water) was administered orally once a day for 15
days (1 day before and 14 days after balloon injury). For assessment of
the intimal area, three cross sections were cut per carotid artery and
stained with hematoxylin-eosin. Cross-sectional intimal areas were
determined with an image analyzer (Luzex 3, Nikon). The mean
value of the intimal or medial areas determined from these three cross
sections was considered the intimal or medial area for each rat.
Statistical Analysis
Data are expressed as mean±SD. Statistical
analyses were performed with one-or two-way ANOVA. When
Bartlett's test for the homogeneity of variances suggested that
within-group variance was not homogeneous among the groups,
a logarithmic transformation was performed to allow for the use of
ANOVA.
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Results |
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Validity of the Competitive RT-PCR Method
The validity of the competitive RT-PCR method has been confirmed in previous studies.19 20 21 Fig 1
illustrates
the validity of the competitive RT-PCR method for the quantification of
ACE mRNA level. Synthetic ACE cRNA combined with various amounts of
synthetic point-mutated ACE cRNA was reverse-transcribed and amplified
by PCR. The observed molar ratio was highly correlated with the molar
ratio of ACE cRNA to point-mutated ACE cRNA
(R2=.984, P<.0001) within the range
examined.
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The PCR products from the carotid arteries 48 hours after balloon injury were directly sequenced and confirmed to correspond to the native mRNAs (renin, AGT, ACE, and AT1aR) (data not shown).
Time Course of RAS mRNA Expression in Balloon-Injured Carotid
Artery
Histological examination at 14 days after balloon
injury revealed marked neointimal formation only in the
balloon-injured (left) carotid artery, which confirmed the validity of
our procedures (Fig 2).
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Fig 3 shows a typical assessment of the expression
levels of RAS mRNA, and Fig 4 summarizes the time course
of the expression levels of RAS mRNA after balloon injury. The renin
mRNA concentration was markedly increased 24 hours after balloon
injury, and an increased renin mRNA concentration was still evident 7
days after balloon injury. The renin mRNA concentration at 14 days
after balloon injury was not significantly higher than that in control
intact carotid artery (Fig 4A). The AT1R mRNA concentration
was significantly increased beginning 3 days after balloon injury and
remained higher than that in the control at 14 days after balloon
injury (Fig 4B). More than 90% of the AT1R mRNA expressed
in the control and balloon-injured arteries consisted of
AT1aR mRNA (data not shown). The ACE mRNA concentration was
decreased 24 hours after balloon injury and increased 14 days after
balloon injury (Fig 4C). No significant change in AGT mRNA
concentration was observed throughout the study period (Fig 4D).
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DNA digested with
HindIII (for rRNA). The quality of sample RNA was confirmed
by ethidium bromide staining as shown in the bottom panel. Lane 1,
Control carotid artery (right side) at 24 hours after balloon injury;
lane 2, balloon-injured carotid artery at 24 hours; lane 3, control at
24 hours; lane 4, balloon-injured at 24 hours; lane 5, control at 3
days; lane 6, balloon-injured at 3 days; lane 7, control at 3 days;
lane 8, balloon-injured at 3 days; lane 9, control at 3 days with
quinapril; lane 10, balloon-injured at 3 days with quinapril; lane 11,
control at 7 days; and lane 12, balloon-injured at 7 days.
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Immunohistochemistry
Immunohistochemical analysis revealed that medial smooth
muscle cells showed renin-like immunoreactivity after balloon injury
(Fig 2B
). This immunoreactivity was evident 24 hours and 3 days after
balloon injury and was not evident 14 days after balloon injury (Fig 2). No significant renin-like immunoreactivity was detected in
neointima (Fig 2C). Occasionally, renin-like
immunoreactivity was detected in adventitia between 1 and 3 days after
balloon injury (Fig 2F). Some of these cells in the adventitia were
stained with OX-42, a monoclonal antibody to
macrophage/monocyte cells (data not shown). This time course of
renin-like immunoreactivity paralleled that of renin mRNA
expression (Figs 2 and 4).
Effects of ACE Inhibitor
On the basis of the above observations, we hypothesized that the
increased renin expression in medial smooth muscle cells after balloon
injury might be responsible for Ang II generation in situ and for the
subsequent events leading to neointimal formation.
Administration of the ACE inhibitor quinapril for 14 days
markedly reduced neointimal formation (Fig 5). Although quinapril administration did not modify
renin mRNA expression in balloon-injured artery, it attenuated the
increase in AT1R mRNA expression at 3, 7, and 14 days after
balloon injury (Fig 6). Likewise, quinapril
administration significantly attenuated the increase in ACE mRNA
expression at 14 days after balloon injury (Fig 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Blockade of the RAS by ACE inhibitors or AT1R antagonists reduces neointimal formation after balloon injury.5 9 10 Moreover, neointimal formation after balloon injury was exaggerated by prolonged Ang II infusion.23 Therefore, it is evident that Ang II is involved in neointimal formation. Induction of gene expression for ACE,12 13 AGT,14 and AT1R15 in the neointima has been reported. The present study reports for the first time that renin expression is transiently induced in the medial smooth muscle cells of balloon-injured carotid artery.
Expression of Renin Gene in Medial Smooth Muscle Cells
Renin mRNA expression was prominently induced in balloon-injured
carotid artery, and renin-like immunoreactivity was detected in medial
smooth muscle cells. We cannot exclude the possibility that renin may
be synthesized in as yet unidentified cells in balloon-injured artery,
and renin may be taken up and concentrated in medial smooth muscle
cells. In fact, cells with renin-like immunoreactivity were
occasionally detected in adventitia between 1 and 3 days after balloon
injury (Fig 2F). We recently reported that monocyte/macrophage
cells infiltrating necrotic myocardium can express
renin.24 Indeed, some of the cells with renin-like
immunoreactivity in the adventitia were positively stained with OX-42,
a monoclonal antibody to monocyte/macrophage cells. However,
infiltration of monocyte/macrophage cells was not a
consistent finding in the samples examined, while the induction
of renin mRNA in balloon-injured carotid artery was observed
consistently. It is well known that, unlike in arteries in
larger animals, thrombus formation and leukocyte infiltration are
minimal in balloon-injured rat artery.25 Moreover, the
expression level of renin mRNA in the adventitia of balloon-injured
carotid artery was not significantly higher than that in the control
carotid artery (data not shown).
Although renin mRNA could not be detected in cultured vascular smooth muscle cells,26 we should not be surprised to find renin gene expression in vascular smooth muscle cells in vivo. Juxtaglomerular cells are known to be modified smooth muscle cells,27 and reninlike immunoreactivity has been detected in vascular smooth muscle cells of fetal intrarenal arteries.28 29
Possible Pathophysiological Significance
Neointimal formation following balloon injury in rat
carotid artery consists of four steps.2 16 17 The first
step is replication of smooth muscle cells in the media, which occurs 0
to 3 days after balloon injury. The second step is migration of smooth
muscle cells from the media to the intima, which occurs 3 to 14 days
after balloon injury. The third and fourth steps are proliferation of
smooth muscle cells and deposition of extracellular matrix in the
neointima, which begins to occur 7 days after balloon
injury. The main mechanism of the inhibition of neointimal
formation by blockade of the RAS involves inhibition of the first two
steps of neointimal formation; ie, medial smooth muscle
replication and migration of medial smooth muscle cells into the
intima.16 17 Thus, it is reasonable to hypothesize that
Ang II generation in situ or Ang II sensitivity in situ may be enhanced
during these two steps.
An increase in the AT1R mRNA concentration was evident beginning 3 days after balloon injury. Viswanathan et al15 reported that neointimal smooth muscle cells expressed fourfold more AT1R than medial smooth muscle cells. The gradual increase in the AT1R mRNA concentration may reflect neointimal formation and/or medial smooth muscle cell replication. In either case, this increase was observed beginning 3 days after balloon injury and could not precede the first step of neointimal formation; ie, medial smooth muscle cell replication.
After denudation of endothelium, the ACE mRNA concentration in the balloon-injured artery was decreased, probably because of a high ACE mRNA concentration in endothelial cells. The ACE mRNA concentration gradually increased with neointimal formation. The site of ACE expression is reportedly vascular smooth muscle cells in the neointima.12 13
On the other hand, the induction of renin gene expression in balloon-injured artery preceded neointimal formation. The time course of renin mRNA expression indicated that renin gene expression was induced in medial smooth muscle cells during the first and second steps of neointimal formation. As described above, blockade of the RAS reduces neointimal formation through inhibition of these two steps.16 17 Therefore, it is conceivable that induced renin in the medial smooth muscle cells may be rate limiting and a key to Ang II generation in situ in balloon-injured rat carotid artery. Assessment of the time course of the Ang II level in balloon-injured carotid artery may be necessary for a definitive answer. This issue requires further investigation.
The increase in the AT1R and ACE mRNA concentrations in balloon-injured artery may be interpreted as a reflection of neointimal formation. Attenuation of this increase by quinapril indicated that this ACE inhibitor could reduce neointimal formation. Since vascular smooth muscle cells in neointima express higher levels of AT1R and ACE mRNAs, reduction of the neointimal area leads to reduced concentrations of AT1R and ACE mRNAs.
Quinapril administration did not cause a further induction of renin mRNA in balloon-injured artery. This indicates that Ang II has no significant effects on renin gene expression in these phenotypically modified vascular smooth muscle cells. It is generally accepted that the expression of a gene is regulated in a tissue-specific manner. Thus, it should be no surprise that the renin gene expression in the medial smooth muscle cells is regulated differently than that in juxtaglomerular cells. The precise molecular mechanisms for the induction of renin gene expression in medial smooth muscle cells remain to be determined. Clarification of these mechanisms may be helpful for identifying new strategies for inhibiting the first two steps of neointimal formation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by a grant-in-aid from the Japanese Ministry of Education, Science, and Culture.
Received May 17, 1996; first decision June 13, 1996; accepted October 14, 1996.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Schwartz SM, Stemerman MB, Benditt EP. The aortic intima, II: repair of the aortic lining after mechanical denudation. Am J Pathol. 1975;81:15-42. [Abstract]
2. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury, I: smooth muscle growth in the absence of endothelium. Lab Invest. 1983;49:327-333. [Medline] [Order article via Infotrieve]
3.
Linder V, Reidy MA. Proliferation of smooth
muscle cells after vascular injury is inhibited by an antibody against
basic fibroblast growth factor. Proc Natl Acad Sci
U S A. 1991;88:3739-3743.
4. Olson NE, Chao S, Linder V, Reidy MA. Intimal smooth muscle cell proliferation after balloon catheter injury: the role of basic fibroblast growth factor. Am J Pathol. 1992;140:1017-1023. [Abstract]
5. Prescott M, Webb R, Reidy MA. ACE inhibitors vs. AII, At1 receptor antagonist: effects on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Pathol. 1991;139:1291-1302. [Abstract]
6.
Fingerle J, Johnson R, Clowes AW, Majesky MW, Reidy
MA. Role of platelets in smooth muscle cell proliferation
and migration after vascular injury in rat carotid artery.
Proc Natl Acad Sci U S A. 1989;86:8412-8416.
7. Clowes AW, Clowes MM, Reidy MA. Kinetics of cellular proliferation after arterial injury, III: endothelial and smooth muscle growth in chronically denuded vessels. Lab Invest. 1986;54:295-303. [Medline] [Order article via Infotrieve]
8. Clowes AW, Reidy MA, Clowes MM. Mechanisms of stenosis after arterial injury. Lab Invest. 1983;49:208-215. [Medline] [Order article via Infotrieve]
9.
Powell J, Clozel J, Muller R, Kuhn H, Hefti F,
Hosang M, Baumgartner HR. Inhibitors of
angiotensin-converting enzyme prevent myointimal
proliferation after vascular injury. Science. 1989;245:186-188.
10.
Kawamura M, Terashita Z, Okuda H, Imura Y, Shino A,
Nakao M, Nishikawa K. TCV-116, a novel angiotensin
II receptor antagonist, prevents intimal thickening and
impairment of vascular function after carotid injury in rats.
J Pharmacol Exp Ther. 1993;266:1664-1669.
11. Schelling P, Fisher PH, Ganten D. Angiotensin and cell growth: a link to cardiovascular hypertrophy. J Hypertens. 1991;9:3-15. [Medline] [Order article via Infotrieve]
12. Rakugi H, Kim DK, Krieger JE, Wang DS, Dzau VJ, Pratt RE. Induction of angiotensin converting enzyme in the neointima after vascular injury: possible role in restenosis. J Clin Invest. 1994;93:339-346.
13. Fishel RS, Thourani V, Eisenberg SJ, Shai SY, Corson MA, Nabel EG, Bernstein KE, Berk BC. Fibroblast growth factor stimulates angiotensin converting enzyme expression in vascular smooth muscle cells. J Clin Invest. 1995;95:377-387.
14.
Rakugi H, Jacob HJ, Krieger JE, Ingelfinger JR, Pratt
RE. Vascular injury induces angiotensinogen gene
expression in the media and neointima.
Circulation. 1993;87:283-290.
15. Viswanathan M, Strömberg C, Seltzer A, Saavedra JM. Balloon angioplasty enhances the expression of angiotensin II AT1 receptors in neointima of rat aorta. J Clin Invest. 1992;90:1707-1712.
16.
Fingerle J, Müller RM, Kuhn H, Pech M,
Baumgartner HR. Mechanism of inhibition of
neointimal formation by the
angiotensin-converting enzyme inhibitor
cilazapril: a study in balloon catheter-injured rat carotid
arteries. Arterioscler Thromb Vasc Biol. 1995;15:1945-1950.
17.
Schwartz SM, deBlois D, O'Brien ER. The intima:
soil for atherosclerosis and
restenosis. Circ Res. 1995;77:445-465.
18. 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]
19. Iwai N, Inagami T, Ohmichi N, Nakamura Y, Saeki Y, Kinoshita M. Differential regulation of rat AT1a and AT1b receptor mRNA. Biochem Biophys Res Commun. 1992;188:298-303. [Medline] [Order article via Infotrieve]
20. Iwai N, Inagami T. Quantitative analysis of renin gene expression in extrarenal tissues by polymerase chain reaction method. J Hypertens. 1992;10:717-724. [Medline] [Order article via Infotrieve]
21.
Iwai N, Shimoike H, Kinoshita M. Cardiac
renin-angiotensin system in the hypertrophied
heart. Circulation. 1995;92:2690-2696.
22.
Naruse M, Takii Y, Inagami T.
Immunohistochemical localization of renin in luteinizing
hormone-producing cells of rat pituitary. Proc Natl Acad
Sci U S A. 1981;78:7579-7583.
23.
Daemen MJAP, Lombardi DM, Schwartz SM.
Angiotensin II induces smooth muscle cell proliferation in
the normal and injured rat arterial wall.
Circ Res. 1991;68:450-456.
24.
Iwai N, Inagami T, Ohmichi N, Kinoshita M. Renin
is expressed in rat monocyte/macrophage cells.
Hypertension. 1996;27:399-403.
25. Jonnason L, Holm J, Hansson GK. Smooth muscle cells express Ia antigen during arterial response to injury. Lab Invest. 1988;6:305-311.
26.
von Lutterotti N, Catanzaro DF, Sealey JE, Laragh
JH. Renin is not synthesized by cardiac and extrarenal vascular
tissues: a review of experimental evidence.
Circulation. 1994;89:458-470.
27. Barajas L, Salido E. Juxtaglomerular apparatus and the renin-angiotensin system. Lab Invest. 1986;54:361-364. [Medline] [Order article via Infotrieve]
28.
Gomez RA, Lynch KR, Sturgill BC, Elwood JP, Chevalier
RL, Carey RM, Peach MJ. Distribution of renin mRNA and its
protein in the developing kidney. Am J Physiol. 1989;257:F850-F858.
29. Tufro-McReddie A, Gomez RA. Ontogeny of the renin-angiotensin system. Semin Nephrol. 1993;13:519-530.[Medline] [Order article via Infotrieve]
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 S. Tazawa, T. Nakane, and S. Chiba Angiotensin II Type 1 Receptor Blockade Prevents Up-Regulation of Angiotensin II Type 1A Receptors in Rat Injured Artery J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 898 - 904. [Abstract] [Full Text]
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F. H. H. Leenen, V. Skarda, B. Yuan, and R. White Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H317 - H325. [Abstract] [Full Text] [PDF]
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