(Circulation. 2000;101:305.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Important Role of Local Angiotensin II Activity Mediated via Type 1 Receptor in the Pathogenesis of Cardiovascular Inflammatory Changes Induced by Chronic Blockade of Nitric Oxide Synthesis in Rats
From the Research Institute of Angiocardiology, Kyushu University Faculty of Medicine, Fukuoka (M.U., K.E., H.T., M. Koyanagi, M. Katoh, H.S., A.T.); the Second Department of Pathology, Kumamoto University School of Medicine, Kumamoto (M.T.); and the Department of Molecular Preventive Medicine, University of Tokyo School of Medicine, Tokyo (K.M.), Japan; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute, Frederick, Md (T.Y.).
Correspondence to Kensuke Egashira, MD, PhD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. e-mail egashira{at}cardiol.med.kyushu-u.ac.jp
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Abstract |
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Background—The chronic inhibition of NO synthesis by N
-nitro-L-arginine methyl
ester (L-NAME) upregulates the cardiovascular tissue
angiotensin II (Ang II)–generating system and induces
cardiovascular inflammatory changes in rats.
Methods and Results—We used a rat model to investigate the role
of local Ang II activity in the pathogenesis of such inflammatory
changes. Marked increases in monocyte infiltration into
coronary vessels and myocardial interstitial areas,
monocyte chemoattractant protein-1 (MCP-1) expression, and nuclear
factor-
B (NF-B, an important redox-sensitive transcriptional
factor that induces MCP-1) activity were observed on day 3 of L-NAME
administration. Along with these changes, vascular superoxide anion
production was also increased. Treatment with an Ang II type 1
receptor antagonist or with a thiol-containing antioxidant,
N-acetylcysteine, prevented all of these changes.
Conclusions—Increased Ang II activity mediated via the type 1 receptor may thus be important in the pathogenesis of early cardiovascular inflammatory changes in this model. Endothelium-derived NO may decrease MCP-1 production and oxidative stress–sensitive signals by suppressing localized activity of Ang II.
Key Words: endothelium-derived factors • nitric oxide • remodeling • proteins • cells
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The vascular endothelium becomes dysfunctional in the early stages of atherosclerosis.1 2 3 4 5 6 7 Such dysfunction has been shown to lead to reduced activity of NO.1 2 A growing body of evidence suggests that endothelium-derived NO regulates the development of vascular structural changes.1 2 8 9 Recently, we observed that inhibition of NO synthesis by N
-nitro-L-arginine
methyl ester (L-NAME) induces a marked monocyte infiltration into the
coronary vessels associated with induction of monocyte
chemoattractant protein-1 (MCP-1) and proliferating cell nuclear
antigen expression.10 The importance of our
observation is supported by the well-recognized concept that the
adhesion of mononuclear cells to, and their infiltration into, the
blood vessel wall are assumed to be crucial early atherogenic
events.11 12
The mechanism of such inflammatory changes after blockade of NO
synthesis is unknown but may be related to the increase in local
activity of angiotensin II (Ang II), because an increase in
activity of ACE and Ang II receptors in the heart and vessels has been
observed during the first week of L-NAME
administration.13 14 However, it has not been established
whether increased Ang II activity is a cause or a result of
cardiovascular inflammatory changes after blockade of
NO synthesis. Recent in vitro studies have demonstrated that the
inhibition of NO synthesis increases oxidative stress,15
activates the transcription regulatory proteins such as nuclear
factor-B (NF-B),16 17 and induces the expression of
various genes, including those encoding adhesion molecules and
inflammatory cytokines18 19 in
endothelial cells. Ang II has been demonstrated to
promote intracellular signaling events that lead to vascular
inflammation, proliferation, and chemotaxis by increasing oxidative
stress through type 1 receptor stimulation.20 21 22 23 24 25
To investigate the role of the local Ang II activity in the pathogenesis of inflammatory changes induced by blockade of NO synthesis, we used a rat model to examine whether blockade of Ang II type 1 receptor prevents such inflammatory changes.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Model of Chronic Inhibition of NO Synthesis
The present study protocol was reviewed and approved by the Committee on Ethics on Animal Experiments, Kyushu University Faculty of Medicine, and the experiments were conducted according to the Guidelines for Animal Experiments of the Kyushu University Faculty of Medicine.
Male Wistar-Kyoto rats 20 weeks old were obtained from an established
colony at the Animal Research Institution of Kyushu University Faculty
of Medicine. Five groups of rats were studied. The control group
received untreated chow and drinking water. The second group (L)
received L-NAME in its drinking water (1 mg/mL). At this concentration,
the daily intake of L-NAME for the latter group was 
30 to 40 mg/d.
The third group (L+ATRA1) received L-NAME in drinking water and a high
dose (75 µg/g) of a selective antagonist of the Ang II
AT1 receptor CS-86626 (a gift from
Sankyo Pharmaceutical Co, Tokyo) in the chow. The fourth group
(L+ATRA2) received L-NAME in the drinking water and a low dose
(7.5 µg/g) of CS-866 in the chow. We found that the high dose of
CS866 prevented the L-NAME–induced increase in systolic
arterial pressure, whereas the low dose of the
antagonist had no effect on such changes27
(Table
). The fifth group (L+NAC) received
L-NAME in the drinking water and a thiol-containing antioxidant,
N-acetylcysteine (NAC), by
intraperitoneal injection (200 mg ·
kg-1 · d-1).
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On day 3 of treatment, systolic blood pressure (by the tail-cuff method), heart rate, and body weight were measured. Then the rats were euthanized for morphometric, immunohistochemical, and biochemical analyses.
Histopathology and Immunohistochemistry
Five rats in each groups were used. The animals were
anesthetized with intraperitoneal
pentobarbital, the heart was perfused via the aorta at a pressure of
90 mm Hg, and the coronary vasculatures were fixed for 60
minutes with methacarn solution.10 28 The heart was
excised and cut into 5 pieces perpendicular to the long axis. All
tissue samples were fixed in methacarn solution for 3 days,
dehydrated, embedded in paraffin, and cut into slices 5 µm
thick. Sections were mounted on glass slides and stained with
hematoxylin-eosin solution for estimation of inflammatory cell
infiltration.
Immunohistochemistry was performed as described.10 28 In brief, paraffin slices 5 µm thick were preincubated with 3% skim milk to decrease nonspecific binding. Sections were immunostained with a mouse anti-rat macrophage/monocyte antibody (ED1, Serotec Inc), a rabbit anti-rat MCP-1 antibody,29 or nonimmune mouse IgG (Zymed Laboratory Inc). Immunohistochemistry for ACE was performed as described.13 After this, tissues were embedded in OCT compound, and sections were immunostained with an antibody for human ACE (10 µg/mL, 9B9, Immunobiology Laboratory Inc) or nonimmune IgG (Zymed Laboratory Inc).
Morphometry and cell enumeration were performed by a single observer who was blind to the treatment protocols as described.10 To quantify the areas affected by inflammatory changes, the hematoxylin-eosin–stained whole-heart sections (5 per heart) were scanned at x40 magnification with a light microscope equipped with a high-resolution video camera (Microphoto-FXA, Nicon). The sum of the areas of inflammatory cell infiltration in each section and the sum of the heart areas in the section were calculated. The areas of large arterial and venous lumen were excluded from this measurement. Then, the percentage of the areas affected by inflammatory cell infiltration in each heart (100xarea affected by inflammatory change/total heart area of the section) was reported.
To quantify the number of ED1-positive monocytes, each section (5 per heart) immunohistochemically stained by an antibody against ED1 was scanned at x40 magnification. The number of ED1-positive cells in each section was counted and summed per heart. The averaged number of the positive cells per section was reported in each animal.
Northern Blot Analysis
Five rats in each group were used. After euthanasia, the hearts
were removed, the atria and great vessels were trimmed away, and the
hearts were snap-frozen in liquid nitrogen and stored at -80°C.
Total RNA was extracted from each sample by the acid guanidinium thiocyanate–phenol-chloroform method (ISOGEN, Nippon Gene), and poly(A)+ RNA was purified on an oligo (dT)–cellulose column (Takara Shuzo). Northern blot hybridization of rat MCP-130 was performed as described.10 Relative amounts of MCP-1 mRNA were normalized against the amounts of GAPDH mRNA.
Electrophoretic Mobility Shift Assays
To determine activation of NF-B binding to the nucleus,
electrophoretic mobility shift assays were performed. Five rats in each
group were used. Nuclear protein extracts were prepared from the aorta
as described.31 The NF-B
oligodeoxynucleotides corresponding to putative consensus
sequences (NF-B: 5'-AGTTGAGGGG-ACTTTCCCAGGC-3', Promega Biotech
Inc) were end-labeled with [32P] dATP and T4
polynucleotide kinase. Labeled
oligonucleotides were column-purified on a Sephadex
G-25 M column (Pharmacia Biotech Inc). Labeled probe (50 000 cpm)
was added to 5 µg of nuclear protein in the presence of a nonspecific
blocker, salmon testes DNA (0.1 µg/µL). The binding reaction also
contained 10 mmol/L Tris-HCl (pH 7.5), 100 mmol/L NaCl,
1 mmol/L EDTA, 0.2% Nonidet P-40, and 0.5 mmol/L DTT. This
mixture was incubated at 25°C for 20 minutes and separated by
electrophoresis on a 5% polyacrylamide gel in
1xTris-glycine-EDTA buffer. Gels were dried and subjected to
autoradiography. Autoradiographs were later subjected
to laser densitometry. Specificity was determined by the addition of
excess cold oligonucleotide (Santa Cruz Biotechnologies
Inc) to the nuclear extracts 10 minutes before addition of radiolabeled
probe.
Measurements of Vascular Superoxide Anion Production
We used the lucigenin chemiluminescence assay to measure
O2- levels in rat
aorta.32 The thoracic aorta was removed en bloc and placed
in cold Krebs-Henseleit solution. The aorta was cut into 5-mm ring
segments and allowed to equilibrate in modified Krebs-HEPES buffer for
10 minutes at 37°C. The O2-
production was measured by the lucigenin
(bis-N-methylacridinium nitrate, 250
µmol/L)–enhanced chemiluminescence technique with a scintillation
counter (Luminescence Reader BLR 301, Aloka Co). To test the
specificity of chemiluminescence reaction, the counts were recorded
after an intracellular superoxide scavenger, Tiron
(4,5-dihydroxy-1,3-benzenedisulfonic acid, 10 µmol/L), was added
to the vial. Signals from the aortic rings were calibrated by use of
known concentrations of xanthine and xanthine oxidase and calculated as
nmol · min-1 · mg-1.
Statistical Analysis
Data are expressed as mean±SEM. Changes in
parameters of a group over time were compared by 1-way
ANOVA and Bonferroni’s multiple comparison test. Differences between
groups were determined with 2-way ANOVA and a multiple comparison test.
A level of P<0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Systolic Arterial Pressure, Heart Rate, and Body Weight
Compared with the control group, the L, L+ATRA2, and L+NAC groups showed a rise in systolic arterial pressure on day 3 of treatment. In the L+ATRA1 group, systolic arterial pressure did not change (Table
).
Histopathology and Immunohistochemistry
Compared with the control group, tissue sections from rats of the
L group exhibited a marked infiltration of mononuclear leukocytes and
fibroblast-like cells into the perivascular areas that immediately
surrounded the coronary vessels (Figure 1). Attachment of mononuclear leukocytes
to the coronary arterial and venous lumen and their
invasion to the vascular medial layer were also observed. Infiltration
of inflammatory cells into myocardial interstitial spaces
was observed.
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We observed no evidence of inflammation in the control rats (Figures 1 and 2). The increase in the
areas of inflammation seen in the L group was significantly inhibited
by the treatment with the low (L+ATRA2 group) and high (L+ATRA1 group)
doses of Ang II AT1 receptor
antagonist or with NAC (L+NAC group).
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P<0.01 vs L
group.
Reaction of cells with antibodies directed against ED1 or MCP-1 was
rarely observed in the control group (Figure 1). We found that
the number of monocytes that had infiltrated into the coronary
vessels and myocardium was markedly increased in the L
group (Figure 2). This increase in monocyte infiltration was
significantly reduced by treatment with the low and high doses of the
Ang II AT1 receptor antagonist or
with NAC. Cells positive for MCP-1 were observed in the vascular intima
and media and in some mononuclear cells that had infiltrated into the
lesion (Figure 1).
In the control group, ACE immunoreactivity was weakly present in
the intimal layer of the aorta (Figure 3). In the L group, the intimal layer and
the perivascular and myocardial inflammatory lesions were intensely
immunoreactive to ACE antibody (Figure 3). No immunoreactivity
was noted when ACE antibody was replaced with nonimmune IgG (data not
shown). In the L+ATRA1 group, no such intense ACE
immunostaining activity was noted (Figure 3).
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Expression of MCP-1 mRNA
In concert with mononuclear cell infiltration, the cardiac MCP-1
mRNA level was markedly increased in the L group (Figure 4). The increased expression of MCP-1
mRNA was reduced in the L+ATRA1 and L+ATRA2 groups.
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O2- Production
O2- production by
the aortic segments with endothelium was greater in the
L group than in the control group (Figure 5). Treatment with the low and high doses
of Ang II AT1 receptor antagonist or
with NAC normalized the L-NAME–induced increase in aortic
O2- production.
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NF-B Activity
Compared with the control group, NF-B binding was increased in
the heart from the L group (Figure 6). The shifted bands were
specific for NF-B, because the addition of 100-fold excess cold
corresponding oligonucleotide to the nuclear extract
abolished the band. The L-NAME–induced increase in NF-B activity in
the L group was prevented by the Ang II AT1
receptor blockade and by antioxidant treatment with NAC.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates for the first time that Ang II type 1 receptor blockade prevents monocyte infiltration into the coronary vessels and myocardial tissues, MCP-1 expression, NF-
B activation, and aortic
O2- production induced
by inhibition of NO synthesis in rats in vivo. We interpret these
findings to suggest that an increase in local activity of Ang II
mediates such early inflammatory changes.
We previously reported activation of cardiovascular ACE
after blockade of NO synthesis.13 In the present
study, we have further demonstrated that ACE is overexpressed in
endothelial cells as well as inflammatory cells that
had appeared in the lesion (monocytes and/or myofibroblasts). In
addition to monocytes, we had found that myofibroblasts expressing
smooth muscle 
-actin and proliferating cell nuclear antigen were
another major cell type that had infiltrated into the inflammatory
lesions.10 14 28 Myofibroblasts are usually transformed
from pericytes or interstitial fibroblasts by transforming
growth factor-ß1 and play an important role in
the development of tissue fibrosis.33 This study clearly
indicated that the increased activity of Ang II due to overexpression
of ACE and subsequent activation of AT1 receptor
induced early inflammatory and proliferative changes in our model.
MCP-1 is known to be a potent chemokine for monocytes34 ;
its expression is induced in atherosclerotic lesions in
vivo.35 36 We found increased MCP-1 immunoreactivity in
endothelial cells, medial smooth muscle cells, and some
inflammatory cells. Thus, the present observation suggests that
increased production of MCP-1 may participate in the monocyte
infiltration into the inflammatory lesions. Our present findings
are in agreement with previous observations by other investigators that
Ang II induces gene expression of MCP-1 in vascular smooth muscle cells
in vitro25 and causes monocyte infiltration into the blood
vessels in vivo.24
Recent in vitro evidence suggests that inhibition of NO synthesis
increases NF-B activity through increased oxidative
stress.16 18 19 25 In the present study, we found that
antioxidant treatment with NAC markedly attenuated the increases in
inflammatory changes and NF-B activity, suggesting that oxidative
stress may be involved in the pathogenesis of NF-B activation in our
in vivo model.
Because inflammatory changes in coronary vessels have been
reported in animal models with hypertension,37
inflammatory changes seen in our experimental model might result at
least in part from the rapid increase in systolic
arterial pressure induced by L-NAME administration. In the
present study, however, a low dose of the AT1
receptor antagonist did not affect the increase in
systolic loading conditions but rather produced an
inhibitory effect identical to that observed with an
antihypertensive high dose of the AT1 receptor
antagonist. We recently found that
AT1 receptor blockade prevented inflammatory
changes and the increase in NF-B activity induced by a lower dose of
L-NAME that had no effect on systolic blood pressure
(unpublished data, 1999). Thus, it is unlikely that the increase in
systolic arterial pressure contributed greatly to
the induction of inflammatory changes in our experimental model.
In conclusion, our present observations suggest that the increase
in the localized Ang II–generating system plays a primary role in
mediating cardiovascular inflammatory changes, MCP-1
expression, oxidative stress, and NF-B activity induced by chronic
inhibition of NO synthesis. We have recently found that NO directly
downregulates Ang II AT1 receptor in vascular
smooth muscle cells.38 Thus, it appears that
endogenous NO that is
physiologically produced by vascular
endothelial cells may decrease MCP-1 production
and oxidative stress–sensitive signals by suppressing localized
activity of Ang II in the blood vessels. The
antiarteriosclerotic and antiatherosclerotic
effects of endothelium-derived NO could be explained by
this mechanism.
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Acknowledgments |
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This study was supported by Grants-in-Aid for Scientific Research (10307019, 10177226, 09877136, and 08457212) from the Ministry of Education, Science, and Culture, Tokyo, Japan.
Received April 27, 1999; revision received July 22, 1999; accepted July 29, 1999.
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 I. F. Benter, M. H. M. Yousif, J. T. Anim, C. Cojocel, and D. I. Diz Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H684 - H691. [Abstract] [Full Text] [PDF]
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 M. Bourraindeloup, C. Adamy, G. Candiani, M. Cailleret, M.-C. Bourin, T. Badoual, J. B. Su, S. Adubeiro, F. Roudot-Thoraval, J.-L. Dubois-Rande, et al. N-Acetylcysteine Treatment Normalizes Serum Tumor Necrosis Factor-{alpha} Level and Hinders the Progression of Cardiac Injury in Hypertensive Rats Circulation, October 5, 2004; 110(14): 2003 - 2009. [Abstract] [Full Text] [PDF]
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Q. Zhao, M. Ishibashi, K.-i. Hiasa, C. Tan, A. Takeshita, and K. Egashira Essential Role of Vascular Endothelial Growth Factor in Angiotensin II-Induced Vascular Inflammation and Remodeling Hypertension, September 1, 2004; 44(3): 264 - 270. [Abstract] [Full Text] [PDF]
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 J. L. Unthank, K. M. Sheridan, and M. C. Dalsing Collateral Growth in the Peripheral Circulation: A Review Vascular and Endovascular Surgery, July 1, 2004; 38(4): 291 - 313. [Abstract] [PDF]
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 H. Ando, J. Zhou, M. Macova, H. Imboden, and J. M. Saavedra Angiotensin II AT1 Receptor Blockade Reverses Pathological Hypertrophy and Inflammation in Brain Microvessels of Spontaneously Hypertensive Rats Stroke, July 1, 2004; 35(7): 1726 - 1731. [Abstract] [Full Text] [PDF]
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 M. Ishibashi, K.-i. Hiasa, Q. Zhao, S. Inoue, K. Ohtani, S. Kitamoto, M. Tsuchihashi, T. Sugaya, I. F. Charo, S. Kura, et al. Critical Role of Monocyte Chemoattractant Protein-1 Receptor CCR2 on Monocytes in Hypertension-Induced Vascular Inflammation and Remodeling Circ. Res., May 14, 2004; 94(9): 1203 - 1210. [Abstract] [Full Text] [PDF]
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 L. Wu, M. Iwai, Z. Li, T. Shiuchi, L.-J. Min, T.-X. Cui, J.-M. Li, M. Okumura, C. Nahmias, and M. Horiuchi Regulation of Inhibitory Protein-{kappa}B and Monocyte Chemoattractant Protein-1 by Angiotensin II Type 2 Receptor-Activated Src Homology Protein Tyrosine Phosphatase-1 in Fetal Vascular Smooth Muscle Cells Mol. Endocrinol., March 1, 2004; 18(3): 666 - 678. [Abstract] [Full Text] [PDF]
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 H. Shimizu, M. Miyoshi, K. Matsumoto, O. Goto, T. Imoto, and T. Watanabe The Effect of Central Injection of Angiotensin-Converting Enzyme Inhibitor and the Angiotensin Type 1 Receptor Antagonist on the Induction by Lipopolysaccharide of Fever and Brain Interleukin-1{beta} Response in Rats J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 865 - 873. [Abstract] [Full Text] [PDF]
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 W. Ni, S. Kitamoto, M. Ishibashi, M. Usui, S. Inoue, K.-i. Hiasa, Q. Zhao, K.-i. Nishida, A. Takeshita, and K. Egashira Monocyte Chemoattractant Protein-1 Is an Essential Inflammatory Mediator in Angiotensin II-Induced Progression of Established Atherosclerosis in Hypercholesterolemic Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 534 - 539. [Abstract] [Full Text]
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J. Yoshida, K. Yamamoto, T. Mano, Y. Sakata, N. Nishikawa, M. Nishio, T. Ohtani, T. Miwa, M. Hori, and T. Masuyama AT1 Receptor Blocker Added to ACE Inhibitor Provides Benefits at Advanced Stage of Hypertensive Diastolic Heart Failure Hypertension, March 1, 2004; 43(3): 686 - 691. [Abstract] [Full Text] [PDF]
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C. Kataoka, K. Egashira, M. Ishibashi, S. Inoue, W. Ni, K.-i. Hiasa, S. Kitamoto, M. Usui, and A. Takeshita Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H768 - H774. [Abstract] [Full Text] [PDF]
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R. Chen, M. Iwai, L. Wu, J. Suzuki, L.-J. Min, T. Shiuchi, T. Sugaya, H.-W. Liu, T.-X. Cui, and M. Horiuchi Important Role of Nitric Oxide in the Effect of Angiotensin-Converting Enzyme Inhibitor Imidapril on Vascular Injury Hypertension, October 1, 2003; 42(4): 542 - 547. [Abstract] [Full Text] [PDF]
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K. Grote, I. Flach, M. Luchtefeld, E. Akin, S. M. Holland, H. Drexler, and B. Schieffer Mechanical Stretch Enhances mRNA Expression and Proenzyme Release of Matrix Metalloproteinase-2 (MMP-2) via NAD(P)H Oxidase-Derived Reactive Oxygen Species Circ. Res., June 13, 2003; 92 (11): e80 - e86. [Abstract] [Full Text] [PDF]
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 M. Miyoshi, K. Nagata, T. Imoto, O. Goto, A. Ishida, and T. Watanabe ANG II is involved in the LPS-induced production of proinflammatory cytokines in dehydrated rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R1092 - R1097. [Abstract] [Full Text] [PDF]
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K. Egashira Molecular Mechanisms Mediating Inflammation in Vascular Disease: Special Reference to Monocyte Chemoattractant Protein-1 Hypertension, March 1, 2003; 41(3): 834 - 841. [Abstract] [Full Text] [PDF]
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 N. Werner and G. Nickenig AT1 receptors in atherosclerosis: biological effects including growth, angiogenesis, and apoptosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A9 - A13. [Abstract] [PDF]
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Q. N. Diep, F. Amiri, R. M. Touyz, J. S. Cohn, D. Endemann, M. F. Neves, and E. L. Schiffrin PPAR{alpha} Activator Effects on Ang II-Induced Vascular Oxidative Stress and Inflammation Hypertension, December 1, 2002; 40(6): 866 - 871. [Abstract] [Full Text] [PDF]
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S. Inoue, K. Egashira, W. Ni, S. Kitamoto, M. Usui, K. Otani, M. Ishibashi, K.-i. Hiasa, K.-i. Nishida, and A. Takeshita Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Limits Progression and Destabilization of Established Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, November 19, 2002; 106(21): 2700 - 2706. [Abstract] [Full Text] [PDF]
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M. Ishibashi, K. Egashira, K.-i. Hiasa, S. Inoue, W. Ni, Q. Zhao, M. Usui, S. Kitamoto, T. Ichiki, and A. Takeshita Antiinflammatory and Antiarteriosclerotic Effects of Pioglitazone Hypertension, November 1, 2002; 40(5): 687 - 693. [Abstract] [Full Text] [PDF]
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R. Nakamura, K. Egashira, Y. Machida, S. Hayashidani, M. Takeya, H. Utsumi, H. Tsutsui, and A. Takeshita Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure: Roles of Oxidative Stress and Inflammation Circulation, July 16, 2002; 106(3): 362 - 367. [Abstract] [Full Text] [PDF]
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S. Wassmann, S. Hilgers, U. Laufs, M. Bohm, and G. Nickenig Angiotensin II Type 1 Receptor Antagonism Improves Hypercholesterolemia-Associated Endothelial Dysfunction Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1208 - 1212. [Abstract] [Full Text] [PDF]
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K. Egashira, Q. Zhao, C. Kataoka, K. Ohtani, M. Usui, I. F. Charo, K.-i. Nishida, S. Inoue, M. Katoh, T. Ichiki, et al. Importance of Monocyte Chemoattractant Protein-1 Pathway in Neointimal Hyperplasia After Periarterial Injury in Mice and Monkeys Circ. Res., June 14, 2002; 90(11): 1167 - 1172. [Abstract] [Full Text] [PDF]
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J. Sadoshima Novel AT1 Receptor-Independent Functions of Losartan Circ. Res., April 19, 2002; 90(7): 754 - 756. [Full Text] [PDF]
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C. Kataoka, K. Egashira, S. Inoue, M. Takemoto, W. Ni, M. Koyanagi, S. Kitamoto, M. Usui, K. Kaibuchi, H. Shimokawa, et al. Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats Hypertension, February 1, 2002; 39(2): 245 - 250. [Abstract] [Full Text] [PDF]
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G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part I: Oxidative Stress and Atherogenesis Circulation, January 22, 2002; 105(3): 393 - 396. [Full Text] [PDF]
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T. Shimosawa, Y. Shibagaki, K. Ishibashi, K. Kitamura, K. Kangawa, S. Kato, K. Ando, and T. Fujita Adrenomedullin, an Endogenous Peptide, Counteracts Cardiovascular Damage Circulation, January 1, 2002; 105(1): 106 - 111. [Abstract] [Full Text] [PDF]
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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L. Wu, M. Iwai, H. Nakagami, Z. Li, R. Chen, J. Suzuki, M. Akishita, M. de Gasparo, and M. Horiuchi Roles of Angiotensin II Type 2 Receptor Stimulation Associated With Selective Angiotensin II Type 1 Receptor Blockade With Valsartan in the Improvement of Inflammation-Induced Vascular Injury Circulation, November 27, 2001; 104(22): 2716 - 2721. [Abstract] [Full Text] [PDF]
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 Y. Quiroz, H. Pons, K. L. Gordon, J. Rincon, M. Chavez, G. Parra, J. Herrera-Acosta, D. Gomez-Garre, R. Largo, J. Egido, et al. Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition Am J Physiol Renal Physiol, July 1, 2001; 281(1): F38 - F47. [Abstract] [Full Text] [PDF]
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A. Tedgui and Z. Mallat Anti-Inflammatory Mechanisms in the Vascular Wall Circ. Res., May 11, 2001; 88(9): 877 - 887. [Abstract] [Full Text] [PDF]
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M. Katoh, K. Egashira, C. Kataoka, M. Usui, M. Koyanagi, S. Kitamoto, Y. Ohmachi, A. Takeshita, and H. Narita Regression by ACE inhibition of arteriosclerotic changes induced by chronic blockade of NO synthesis in rats Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2306 - H2312. [Abstract] [Full Text] [PDF]
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W. Ni, K. Egashira, S. Kitamoto, C. Kataoka, M. Koyanagi, S. Inoue, K. Imaizumi, C. Akiyama, K.-i. Nishida, and A. Takeshita New Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, April 24, 2001; 103(16): 2096 - 2101. [Abstract] [Full Text] [PDF]
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M. Koyanagi, K. Egashira, S. Kitamoto, W. Ni, H. Shimokawa, M. Takeya, T. Yoshimura, and A. Takeshita Role of Monocyte Chemoattractant Protein-1 in Cardiovascular Remodeling Induced by Chronic Blockade of Nitric Oxide Synthesis Circulation, October 31, 2000; 102(18): 2243 - 2248. [Abstract] [Full Text] [PDF]
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 K. EGASHIRA, M. KOYANAGI, S. KITAMOTO, W. NI, C. KATAOKA, R. MORISHITA, Y. KANEDA, C. AKIYAMA, K.-I. NISHIDA, K. SUEISHI, et al. Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis FASEB J, October 1, 2000; 14(13): 1974 - 1978. [Abstract] [Full Text]
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T. Watanabe, M. Hashimoto, M. Wada, T. Imoto, M. Miyoshi, D. Sadamitsu, and T. Maekawa Angiotensin-converting enzyme inhibitor inhibits dehydration-enhanced fever induced by endotoxin in rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2000; 279(4): R1512 - R1516. [Abstract] [Full Text] [PDF]
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S. Kitamoto, K. Egashira, C. Kataoka, M. Koyanagi, M. Katoh, H. Shimokawa, R. Morishita, Y. Kaneda, K. Sueishi, and A. Takeshita Increased Activity of Nuclear Factor-{kappa}B Participates in Cardiovascular Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis in Rats Circulation, August 15, 2000; 102(7): 806 - 812. [Abstract] [Full Text] [PDF]
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J. Sadoshima Cytokine Actions of Angiotensin II Circ. Res., June 23, 2000; 86(12): 1187 - 1189. [Full Text] [PDF]
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M. Kubo-Inoue, K. Egashira, M. Usui, M. Takemoto, K. Ohtani, M. Katoh, H. Shimokawa, and A. Takeshita Long-term inhibition of nitric oxide synthesis increases arterial thrombogenecity in rat carotid artery Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1478 - H1484. [Abstract] [Full Text] [PDF]
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Q. Zhao, K. Egashira, S. Inoue, M. Usui, S. Kitamoto, W. Ni, M. Ishibashi, K.-i. Hiasa, T. Ichiki, M. Shibuya, et al. Vascular Endothelial Growth Factor Is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis Circulation, March 5, 2002; 105(9): 1110 - 1115. [Abstract] [Full Text] [PDF]
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