Vascular Biology |
Presented in part at the annual spring meeting of the German Society of Heart Research, Mannheim, Germany, April 35, 1997, and at the 70th Scientific Sessions of the American Heart Association, Orlando, Florida, November 912, 1997.
From the Departments of Cardiology (R.K., J.S., C.A.H.P, W.K.) and Cardiac Surgery (S.H.), University of Heidelberg, Heidelberg, Germany; and the Vascular Medicine and Atherosclerosis Unit (P.L.), Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Correspondence to Roger Kranzhöfer, MD, Department of Cardiology, University of Heidelberg, Bergheimer Str 58, 69115 Heidelberg, Germany. E-mail roger_kranzhoefer{at}med.uni-heidelberg.de
| Abstract |
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B in
electrophoretic mobility shift assays. Angiotensin II
concentration-dependently (1 nmol/L to 1 µmol/L) stimulated IL-6
production by SMCs via activation of the
angiotensin II type 1 receptor (demonstrated by the
inhibitory action of the receptor antagonist
losartan). Angiotensin I increased IL-6
production by SMCs, too. This effect was inhibited by captopril
and ramiprilat, suggesting conversion of
angiotensin I to angiotensin II by
angiotensin-converting enzyme in SMCs. Steady-state mRNA
for IL-6 was augmented after stimulation with angiotensin
II, suggesting regulation of angiotensin-induced IL-6
release at the pretranslational level. Moreover, the proinflammatory
transcription factor nuclear factor-
B, which is necessary for
transcription of most cytokine genes, was also
activated by angiotensin II. Pyrrolidine
dithiocarbamate suppressed angiotensin IIinduced IL-6
release, a finding compatible with involvement of reactive oxygen
species as second messengers in cytokine production
mediated by angiotensin. The data demonstrate the ability
of angiotensin to elicit an inflammatory response in human
vascular SMCs by stimulation of cytokine production and
activation of nuclear factor-
B. Inflammatory activation of the
vessel wall by a dysregulated renin-angiotensin system may
contribute to the pathogenesis of atherosclerosis.
Key Words: angiotensin atherosclerosis inflammation interleukins smooth muscle nuclear factor-
B
| Introduction |
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Most studies on the mechanisms underlying the atherogenic effect of the renin-angiotensin system have focused on angiotensin-induced hyperplasia and hypertrophy of vascular smooth muscle cells (SMCs),12 13 presumably mediated by classic growth factors.14 15 Atherosclerosis, however, is also characterized by chronic inflammation of the vessel wall.16 17 Cytokines are regarded as important modulators of inflammatory events occurring during all stages of atherogenesis.18 19 Numerous studies have shown that SMCs, in addition to leukocytes, can be an important source of cytokines in the vessel wall.20 21 22 23 24 Some factors linked to atherosclerosis are known to augment cytokine production in SMCs, eg, oxidatively modified LDL or thrombin.25 26 This study tested the hypothesis that another pathophysiologically relevant mediator, angiotensin, stimulates inflammatory activation and cytokine production in human vascular SMCs. Production of interleukin-6 (IL-6), which is a potent stimulus of the acute-phase reaction, an important activator of lymphocytes,27 and an inducer of collagen and glycosaminoglycan production in fibroblasts,28 was used as marker of the proinflammatory potential of SMCs.
| Methods |
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Materials
Angiotensin II, angiotensin I,
captopril, and pyrrolidine dithiocarbamate (PDTC) were from Sigma.
Losartan was a gift from Merck, ramiprilat a gift
from Astra. Recombinant human tumor necrosis factor-
(TNF
) was
purchased from Endogen. Testing for bacterial endotoxin with the
Limulus amebocyte lysate assay (BioWhittaker) revealed
levels
0.25 EU/mL for all agents.
Determination of IL-6 Release
SMCs were grown in 96-well plates to confluency and kept in
insulintransferrin medium for 2 days before the experiment. After
addition of the stimuli, cells were incubated for 24 hours, then the
conditioned medium was collected and frozen. Assays for IL-6 were
performed with an enzyme-linked immunosorbent assay kit (Endogen)
according to the manufacturer's instructions. The assay selectively
recognizes IL-6, with a limit of detection of <1 pg/mL.
RNA Isolation and RT-PCR
Confluent SMCs in 10-cm Petri dishes were used for total RNA
extraction, using RNAzol (Wak-Chemie) according to the manufacturer's
instructions. Complementary DNA was synthesized from 1-µg samples of
total RNA (1 µg) by using Moloney murine leukemia virus reverse
transcriptase (Fermentas). Specific cDNA from the reverse transcriptase
reaction product was amplified by using human IL-6specific
primers (5'-ATGAACTCCTTCTCCACAAGCGC-3' and
5'-GAAGAGCCCTCAGGCTGGACTG-3') and
glyceraldehyde-3-phosphate dehydrogenasespecific
primers (5'-CCACCCATGGCAAATTCCATGGCA-3' and
5'-TGCTAAGCAGTTGGTGGTGCAGGAG-3'). Amplification was performed with
Taq DNA polymerase (Fermentas) in a DNA thermal cycler (Stratagene)
with 34 cycles consisting of 45 seconds at 94°C, 45 seconds at
65°C, and 1.5 minutes at 72°C. The amplification products were
electrophoresed on 1% agarose and visualized by ethidium bromide
staining. The predicted size of the products was 622 bp for the
IL-6 gene and 212 bp for the glyceraldehyde-3-phosphate
dehydrogenase gene.
Electrophoretic Mobility Shift Assay
Protein extracts from SMCs were prepared as follows: After
washing in ice-cold PBS 3 times, the cells were scraped off the tissue
culture dish, resuspended, and sedimented by
centrifugation. The cell pellet was lysed in a buffer
composed of 20 mmol/L HEPES-KOH (pH 7.9), 0.35 mol/L NaCl, 20%
glycerol, 1% NP-40, 1 mmol/L MgCl2,
0.5 mmol/L EDTA, 0.5 mmol/L EGTA, 10 µg/mL leupeptin,
0.5 mmol/L DTT, and 0.2 mmol/L PMSF by incubation on ice for
30 minutes. After centrifugation, the supernatant
containing the protein fraction was frozen at -80°C. For
electrophoretic mobility shift assays, a double-stranded
oligonucleotide (Promega) representing the
consensus sequence for nuclear factor-
B (NF-
B) binding was
labeled with [
-32P]ATP (NEN), using T-4
polynucleotide kinase (Promega). Cell proteins (10 µg)
and labeled oligonucleotide (50 000 to 70 000 cpm)
were incubated for binding of active NF-
B for 20 minutes at room
temperature in a buffer containing 20 µg
poly(deoxy-inosinic:deoxy-cytidylic acid), 8% Ficoll 400,
44 mmol/L HEPES-KOH (pH 7.9), 140 mmol/L KCl, 4% glycerol,
0.05% NP-40, 0.1 mmol/L EDTA, 4.4 mmol/L DTT, and 0.06
mmol/L PMSF. Immediately after binding, the protein/DNA complexes were
separated from unbound oligonucleotide by
electrophoresis on a native 5% polyacrylamide gel in
TRIS boric acid EDTA buffer. Autoradiography was
performed with the dried gels by using Hyperfilm (Amersham). For
testing of specificity of NF-
B/DNA binding, in some experiments,
antibodies (Santa Cruz Biotechnology) against the p65 or p50 subunits
of NF-
B were added to the proteins, resulting in further retardation
of electrophoretic mobility, or a 160-fold molar excess of unlabeled
oligonucleotide was added to the binding reaction,
leading to a decrease in NF-
Bbound radioactivity.
Statistical Analysis
Numeric results are expressed as arithmetic mean±SEM values.
Statistical difference was analyzed by ANOVAs followed by
Fisher's exact test. A P value of <0.05 was considered
significant.
| Results |
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(20 ng/mL). Four experiments with cells from different
donors gave similar results.
|
Angiotensin IIInduced IL-6 Release From SMCs Depends
on the Angiotensin II Type 1 Receptor
Most effects of angiotensin on vascular SMCs are
mediated by the angiotensin II type 1 receptor.
Losartan (1 and 10 µmol/L), a selective
angiotensin II type 1 receptor antagonist,
reduced angiotensin IIstimulated IL-6 release from SMCs
(Figure 2
). This finding demonstrates
both specificity of the angiotensin II effect and
involvement of the type 1 receptor.
|
Angiotensin I Stimulates IL-6 Release by SMCs via an
Angiotensin-Converting EnzymeDependent Mechanism
Because ACE is present in human
atheroma,1 we investigated the effect of
angiotensin I on cytokine production. In a
similar manner to angiotensin II, angiotensin I
(100 nmol/L to 10 µmol/L) stimulated IL-6 release from SMCs,
with a concentrationresponse curve shifted to the right compared with
angiotensin II. Angiotensin Iinduced IL-6
production was suppressed by 2 different ACE
inhibitors, captopril (10 µmol/L) and
ramiprilat (1 µmol/L) (Figure 3
). This finding demonstrates that the
angiotensin I effect depends on conversion of
angiotensin I to angiotensin II and is mediated
by ACE present in active form in cultured SMCs. The observation is
of particular interest, because another enzyme, chymase, has been
implicated in angiotensin conversion in blood
vessels.31
|
Angiotensin Stimulates Accumulation of IL-6
mRNA
Most cytokines are regulated mainly at the transcriptional
level. Therefore, we examined the effect of angiotensin II
on IL-6 mRNA in SMCs by RT-PCR. Both TNF
(20 ng/mL) and
angiotensin II (1 µmol/L) increased steady-state
IL-6 mRNA levels compared with control conditions, whereas the
constitutively expressed glyceraldehyde-3-phosphate
dehydrogenase gene was not upregulated by these agents (Figure 4
). Actinomycin D (5 µg/mL) completely
blocked angiotensin II and TNF
-stimulated increase of
IL-6 mRNA, suggesting that IL-6 expression is dependent on
transcriptional regulation (data not shown).
|
Angiotensin II Activates the Transcription
Factor NF-
B
Activation of NF-
B was probed by electrophoretic mobility shift
assay (Figure 5
). Both TNF
and, to a
lesser extent, angiotensin II activated NF-
B in
SMCs. Active NF-
B was already present after 30 minutes of
stimulation. Maximal NF-
B activation was found after 1 hour of
stimulation and was still present after 2 hours (Figure 5A
).
The specificity of the shifted autoradiographic bands was
ascertained in 2 ways. (1) Addition of antibodies against the p65
subunit or the p50 subunit (not shown) of NF-
B resulted in a further
retardation of the mobility of the
NF-
B/oligonucleotide complex ("supershift"). (2)
An excess of unlabeled oligonucleotide reduced the
signal intensity of the band associated with active NF-
B (Figure 5B
).
|
PDTC Inhibits Angiotensin IIInduced IL-6
Release
Activation of NF-
B (and subsequent production of
cytokines) can also be mediated by reactive oxygen
species.32 33 We therefore examined the effect of the
radical scavenger PDTC on angiotensin IIinduced IL-6
release by vascular SMCs (Figure 6
). At
10 µmol/L, PDTC reduced IL-6 accumulation both under control
conditions and with stimulation by TNF
or angiotensin
II; 25 µmol/L PDTC virtually abolished IL-6 release caused by
either angiotensin II or TNF
. The results suggest the
involvement of oxygen radicals in both basal and stimulated IL-6
secretion.
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| Discussion |
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B, a transcription factor system
commonly involved in inflammatory and immune responses.
Mechanisms usually ascribed to angiotensin's atherogenic
action include stimulation of SMC mitogenesis or
hypertrophy,12 34 induction of growth factors
and protooncogenes,14 15 augmented extracellular matrix
synthesis,35 and interaction with the fibrinolytic
system.36 These observations were made in rat SMCs,
leaving some uncertainty as to whether the same mechanisms apply to
human tissue. A recent study demonstrated increased mRNA expression for
the chemokine MCP-1 in rat vascular SMCs on angiotensin II
stimulation.37 In a similar manner, Moriyama et
al38 described IL-6 release from mouse
mesangial cells stimulated by angiotensin II.
To our knowledge, the present study is the first to describe
inflammatory activation of human vascular SMCs by
angiotensin. Other potentially important inflammatory
actions of angiotensin II include stimulation of TNF
release by blood monocytes and increased adherence of monocytes to
endothelial cells.39 Inflammatory
responses mediated by cytokines are presumably important in all
stages of atherosclerosis. Monocyte adherence to the
endothelium and infiltration of the vessel wall,
probably the first step leading to the development of the fatty streak,
depends on endothelial expression of adhesion
molecules, an event that is regulated by
cytokines.40 In advanced stages of
atherosclerosis, cytokines may promote
destabilization and rupture of plaques by induction of matrix-degrading
enzymes, ultimately leading to thrombosis and complete obstruction of
the vessel.19 Stimulation of cytokine
production by angiotensin could contribute to these
events. Increased production of IL-6 may be of particular
clinical relevance, because the acute-phase reaction, eg, synthesis of
C-reactive protein by the liver, is regulated mainly by
IL-6.27 Data from the Physician's Health Study showed
that the plasma level of C-reactive protein in apparently healthy men
predicts the risk of future myocardial infarction and
stroke.41 Moreover, increased blood concentrations of IL-6
in patients with unstable angina correlated with C-reactive protein
levels.42 IL-6 production by the vessel wall may
be an important mediator of local and generalized inflammatory
reactions in the evolution of acute coronary syndromes.
Moreover, stimulation of lymphocytes by IL-6 may be equally important,
because activated T lymphocytes are present in human
atheroma and probably contribute to ongoing inflammation
within the plaque, ultimately leading to its
rupture.43 44 45
Another interesting result of this study is that
angiotensin I also stimulated IL-6 production in
SMCs by an ACE-dependent mechanism, indicating the presence of active
ACE in cultured human SMCs. Suppression of inflammatory responses in
the vessel wall can explain in part the beneficial action of ACE
inhibitors on myocardial reinfarction rates observed in the
Studies of Left Ventricular Dysfunction and Survival and
Ventricular Enlargement (Study) trials.8 9 10 However, in
the intact artery lined with endothelium, the situation
may be more complicated. Hernández-Presa et al37
demonstrated in a rabbit model of early atherosclerosis
that the ACE inhibitor quinapril reduced monocyte
accumulation, MCP-1 expression, and NF-
B activation in the vessel
wall. These findings could result from either decreased stimulation of
vessel wall cells by angiotensin II or increased
accumulation of bradykinin because of suppression of its breakdown by
ACE inhibitors. Bradykinin is known to stimulate
endothelial production of nitric
oxide,46 a molecule that can suppress inflammatory
activation of vascular SMCs.47 Our data provide evidence
for an antiinflammatory action of ACE inhibitors affecting
SMCs directly. Further in vivo experiments comparing the effects of ACE
inhibitors with those of angiotensin II type 1
receptor blockers and bradykinin receptor antagonists could
clarify the contribution of the different pathways.
IL-6 production, as well as the synthesis of other
cytokines, is regulated at the transcriptional level. The
promoter regions of cytokine genes commonly contain binding
sequences for the transcription factor NF-
B.48
Transcription of the IL-6 gene also depends on NF-
B.49
Activated NF-
B is present in human
atheroma50 and human vascular SMCs express
inducible NF-
B activity.51 We report here activation of
NF-
B in human vascular SMCs by angiotensin II.
Activation of NF-
B is a point of convergence by which different
atherogenic agents cause inflammatory activation of the vessel
wall.52 At present, it remains unclear by which
intracellular signaling pathway angiotensin induces NF-
B
and IL-6 production. NF-
B can possibly be activated
through phosphorylation by protein kinase
C,48 which is stimulated by angiotensin
II.53 Preliminary data presented in abstract form
suggest involvement of the JAK/STAT pathway for induction of IL-6
production in SMCs.54 Another way in which
angiotensin may signal NF-
B activation is through
stimulation of NADH and NADPH oxidases, enzymes that generate
O2-.55 Reactive
oxygen species are regarded as second messengers for the activation of
NF-
B32 and for the expression of
cytokines.33 Our work demonstrated inhibition of
angiotensin IIinduced IL-6 release by the radical
scavenger PDTC. This finding is compatible with the hypothesis that
reactive oxygen intermediates participate in angiotensin
IIstimulated cytokine production by vascular SMCs.
Further work is required to dissect the intracellular signal pathways
that transmit angiotensin-mediated inflammatory
activation.
In summary, the present data show that dysregulation of the local renin-angiotensin system may initiate and promote atherosclerosis by inflammatory activation of the vessel wall. Thus, angiotensin must be regarded as more than a regulator of vascular tone, but as a mediator affecting the local biology of the arterial wall by triggering inflammatory pathways. Suppression of angiotensin's proinflammatory action on vascular tissue could in part explain the beneficial effect of ACE inhibitors on recurrence of myocardial infarction.
| Acknowledgments |
|---|
Received July 29, 1998; accepted November 26, 1998.
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K. R. Chava, M. Karpurapu, D. Wang, M. Bhanoori, V. Kundumani-Sridharan, Q. Zhang, T. Ichiki, W. C. Glasgow, and G. N. Rao CREB-Mediated IL-6 Expression Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-Induced Vascular Smooth Muscle Cell Migration Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 809 - 815. [Abstract] [Full Text] [PDF] |
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Y. C. Chan and P. S. Leung Involvement of Redox-Sensitive Extracellular-Regulated Kinases in Angiotensin II-Induced Interleukin-6 Expression in Pancreatic Acinar Cells J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 450 - 458. [Abstract] [Full Text] [PDF] |
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B. Ponnuchamy and R. A. Khalil Cellular mediators of renal vascular dysfunction in hypertension Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R1001 - R1018. [Abstract] [Full Text] [PDF] |
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M. Zhang, S.-h. Zhou, S.-P. Zhao, Q.-m. Liu, X.-p. Li, and X.-Q. Shen Irbesartan attenuates Ang II-induced BMP-2 expression in human umbilical vein endothelial cells Vascular Medicine, August 1, 2008; 13(3): 239 - 245. [Abstract] [PDF] |
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R. C Parish and J. D Evans Inflammation in Chronic Heart Failure Ann. Pharmacother., July 1, 2008; 42(7): 1002 - 1016. [Abstract] [Full Text] [PDF] |
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D. D. Pearse, R.-X. Tian, J. Nigro, J. B. Iorgulescu, L. Puzis, and E. A. Jaimes Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1094 - F1100. [Abstract] [Full Text] [PDF] |
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M. J. Haurani and P. J. Pagano Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res, September 1, 2007; 75(4): 679 - 689. [Abstract] [Full Text] [PDF] |
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S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF] |
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K. Ohwaki, H. Bujo, M. Jiang, H. Yamazaki, W. J. Schneider, and Y. Saito A Secreted Soluble Form of LR11, Specifically Expressed in Intimal Smooth Muscle Cells, Accelerates Formation of Lipid-Laden Macrophages Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1050 - 1056. [Abstract] [Full Text] [PDF] |
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R. Tkacova and P. Joppa Angiotensin-converting enzyme genotype and C-reactive protein in patients with COPD Eur. Respir. J., April 1, 2007; 29(4): 816 - 817. [Full Text] [PDF] |
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D. Wang, Z. Liu, Q. Li, M. Karpurapu, V. Kundumani-Sridharan, H. Cao, N. Dronadula, F. Rizvi, A. K. Bajpai, C. Zhang, et al. An Essential Role for gp130 in Neointima Formation Following Arterial Injury Circ. Res., March 30, 2007; 100(6): 807 - 816. [Abstract] [Full Text] [PDF] |
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H.-Y. Yang, P.-F. Kao, T.-H. Chen, B. Tomlinson, W.-C. Ko, and P. Chan Effects of the Angiotensin II Type 1 Receptor Antagonist Valsartan on the Expression of Superoxide Dismutase in Hypertensive Patients J. Clin. Pharmacol., March 1, 2007; 47(3): 397 - 403. [Abstract] [Full Text] [PDF] |
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J. Ruef, M. Browatzki, C. A. Pfeiffer, J. Schmidt, and R. Kranzhofer Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2 Vascular Medicine, February 1, 2007; 12(1): 23 - 27. [Abstract] [PDF] |
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Z. Orosz, A. Csiszar, N. Labinskyy, K. Smith, P. M. Kaminski, P. Ferdinandy, M. S. Wolin, A. Rivera, and Z. Ungvari Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H130 - H139. [Abstract] [Full Text] [PDF] |
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P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF] |
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P. Libby and P. M. Ridker Inflammation and Atherothrombosis: From Population Biology and Bench Research to Clinical Practice J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A33 - A46. [Abstract] [Full Text] [PDF] |
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P. M Ridker, E. Danielson, N. Rifai, R. J. Glynn, and for the Val-MARC Investigators Valsartan, Blood Pressure Reduction, and C-Reactive Protein: Primary Report of the Val-MARC Trial Hypertension, July 1, 2006; 48(1): 73 - 79. [Abstract] [Full Text] [PDF] |
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V Teplitsky, Y Shoenfeld, and A Tanay The renin-angiotensin system in lupus: physiology, genes and practice, in animals and humans Lupus, June 1, 2006; 15(6): 319 - 325. [Abstract] [PDF] |
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A. Douillette, A. Bibeau-Poirier, S.-P. Gravel, J.-F. Clement, V. Chenard, P. Moreau, and M. J. Servant The Proinflammatory Actions of Angiotensin II Are Dependent on p65 Phosphorylation by the I{kappa}B Kinase Complex J. Biol. Chem., May 12, 2006; 281(19): 13275 - 13284. [Abstract] [Full Text] [PDF] |
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S. Kumar, S. Savitz, G. Schlaug, L. Caplan, and M. Selim Antiplatelets, ACE inhibitors, and statins combination reduces stroke severity and tissue at risk Neurology, April 25, 2006; 66(8): 1153 - 1158. [Abstract] [Full Text] [PDF] |
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M. Hermann and F. Ruschitzka Novel anti-inflammatory drugs in hypertension Nephrol. Dial. Transplant., April 1, 2006; 21(4): 859 - 864. [Full Text] [PDF] |
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S. G. Tsouli, E. N. Liberopoulos, D. N. Kiortsis, D. P. Mikhailidis, and M. S. Elisaf Combined Treatment With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers: A Review of the Current Evidence Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 1 - 15. [Abstract] [PDF] |
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D. L. Lee, L. C. Sturgis, H. Labazi, J. B. Osborne Jr., C. Fleming, J. S. Pollock, M. Manhiani, J. D. Imig, and M. W. Brands Angiotensin II hypertension is attenuated in interleukin-6 knockout mice Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H935 - H940. [Abstract] [Full Text] [PDF] |
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C. J. Boos, R. A. Anderson, and G. Y.H. Lip Is atrial fibrillation an inflammatory disorder? Eur. Heart J., January 2, 2006; 27(2): 136 - 149. [Abstract] [Full Text] [PDF] |
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O Wazni, D O Martin, N F Marrouche, M Shaaraoui, M K Chung, S Almahameed, R A Schweikert, W I Saliba, and A Natale C reactive protein concentration and recurrence of atrial fibrillation after electrical cardioversion Heart, October 1, 2005; 91(10): 1303 - 1305. [Abstract] [Full Text] [PDF] |
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J. Amar, J.-B. Ruidavets, J.-C. Peyrieux, J.-M. Mallion, J. Ferrieres, M. E. Safar, and B. Chamontin C-Reactive Protein Elevation Predicts Pulse Pressure Reduction in Hypertensive Subjects Hypertension, July 1, 2005; 46(1): 151 - 155. [Abstract] [Full Text] [PDF] |
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L. Zhang, Y. Ma, J. Zhang, J. Cheng, and J. Du A New Cellular Signaling Mechanism for Angiotensin II Activation of NF-{kappa}B: An I{kappa}B-Independent, RSK-Mediated Phosphorylation of p65 Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1148 - 1153. [Abstract] [Full Text] [PDF] |
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M. F. Walter, R. F. Jacob, B. Jeffers, M. M. Ghadanfar, G. M. Preston, J. Buch, and R. P. Mason Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease: A longitudinal analysis of the PREVENT study J. Am. Coll. Cardiol., November 16, 2004; 44(10): 1996 - 2002. [Abstract] [Full Text] [PDF] |
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Y. Chen, A.-P. Arrigo, and R. W. Currie Heat shock treatment suppresses angiotensin II-induced activation of NF-{kappa}B pathway and heart inflammation: a role for IKK depletion by heat shock? Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1104 - H1114. [Abstract] [Full Text] [PDF] |
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D. L. Lee, R. Leite, C. Fleming, J. S. Pollock, R. C. Webb, and M. W. Brands Hypertensive Response to Acute Stress Is Attenuated in Interleukin-6 Knockout Mice Hypertension, September 1, 2004; 44(3): 259 - 263. [Abstract] [Full Text] [PDF] |
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E. L. Schiffrin and R. M. Touyz From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H435 - H446. [Full Text] [PDF] |
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M. Mazighi, A. Pelle, W. Gonzalez, E. M. Mtairag, M. Philippe, D. Henin, J.-B. Michel, and L. J. Feldman IL-10 inhibits vascular smooth muscle cell activation in vitro and in vivo Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H866 - H871. [Abstract] [Full Text] [PDF] |
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H. Hashimoto, K. Kitagawa, H. Hougaku, H. Etani, and M. Hori Relationship Between C-Reactive Protein and Progression of Early Carotid Atherosclerosis in Hypertensive Subjects Stroke, July 1, 2004; 35(7): 1625 - 1630. [Abstract] [Full Text] [PDF] |
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P. Sivashanmugam, L. Tang, and Y. Daaka Interleukin 6 Mediates the Lysophosphatidic Acid-regulated Cross-talk between Stromal and Epithelial Prostate Cancer Cells J. Biol. Chem., May 14, 2004; 279(20): 21154 - 21159. [Abstract] [Full Text] [PDF] |
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B. Jiang, S. Xu, X. Hou, D. R. Pimentel, and R. A. Cohen Angiotensin II Differentially Regulates Interleukin-1-{beta}-inducible NO Synthase (iNOS) and Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression: ROLE OF p38 MAPK J. Biol. Chem., May 7, 2004; 279(19): 20363 - 20368. [Abstract] [Full Text] [PDF] |
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F. O'Rourke, N. Dean, N. Akhtar, and A. Shuaib Current and future concepts in stroke prevention Can. Med. Assoc. J., March 30, 2004; 170(7): 1123 - 1133. [Abstract] [Full Text] [PDF] |
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R. Candido, T. J. Allen, M. Lassila, Z. Cao, V. Thallas, M. E. Cooper, and K. A. Jandeleit-Dahm Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis Circulation, March 30, 2004; 109(12): 1536 - 1542. [Abstract] [Full Text] [PDF] |
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A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF] |
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G. J. Blake, N. Rifai, J. E. Buring, and P. M Ridker Blood Pressure, C-Reactive Protein, and Risk of Future Cardiovascular Events Circulation, December 16, 2003; 108(24): 2993 - 2999. [Abstract] [Full Text] [PDF] |
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M. Di Napoli and F. Papa Association Between Blood Pressure and C-Reactive Protein Levels in Acute Ischemic Stroke Hypertension, December 1, 2003; 42(6): 1117 - 1123. [Abstract] [Full Text] [PDF] |
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P. E. Szmitko, C.-H. Wang, R. D. Weisel, J. R. de Almeida, T. J. Anderson, and S. Verma New Markers of Inflammation and Endothelial Cell Activation: Part I Circulation, October 21, 2003; 108(16): 1917 - 1923. [Full Text] [PDF] |
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B. Martin-McNulty, D. M. Tham, V. da Cunha, J. J. Ho, D. W. Wilson, J. C. Rutledge, G. G. Deng, R. Vergona, M. E. Sullivan, and Y.-X. Wang 17{beta}-Estradiol Attenuates Development of Angiotensin II-Induced Aortic Abdominal Aneurysm in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1627 - 1632. [Abstract] [Full Text] [PDF] |
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D. S. Jacoby and D. J. Rader Renin-Angiotensin System and Atherothrombotic Disease: From Genes to Treatment Arch Intern Med, May 26, 2003; 163(10): 1155 - 1164. [Abstract] [Full Text] [PDF] |
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G. G. Deng, B. Martin-McNulty, D. A. Sukovich, A. Freay, M. Halks-Miller, T. Thinnes, D. J. Loskutoff, P. Carmeliet, W. P. Dole, and Y.-X. Wang Urokinase-Type Plasminogen Activator Plays a Critical Role in Angiotensin II-Induced Abdominal Aortic Aneurysm Circ. Res., March 21, 2003; 92(5): 510 - 517. [Abstract] [Full Text] [PDF] |
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R. De Caterina and C. Manes Inflammation in early atherogenesis: impact of ACE inhibition Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A15 - A24. [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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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF] |
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A. R. Brasier, A. Recinos III, and M. S. Eledrisi Vascular Inflammation and the Renin-Angiotensin System Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1257 - 1266. [Abstract] [Full Text] [PDF] |
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C. Viedt, J. Vogel, T. Athanasiou, W. Shen, S. R. Orth, W. Kubler, and J. Kreuzer Monocyte Chemoattractant Protein-1 Induces Proliferation and Interleukin-6 Production in Human Smooth Muscle Cells by Differential Activation of Nuclear Factor-{kappa}B and Activator Protein-1 Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 914 - 920. [Abstract] [Full Text] [PDF] |
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF] |
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D J Brull, J Sanders, A Rumley, G D Lowe, S E Humphries, and H E Montgomery Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release Heart, March 1, 2002; 87(3): 252 - 255. [Abstract] [Full Text] [PDF] |
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, V. Esteban, Y. Suzuki, S. Mezzano, J.J. Plaza, and J. Egido Role of the Renin-Angiotensin System in Vascular Diseases: Expanding the Field Hypertension, December 1, 2001; 38(6): 1382 - 1387. [Abstract] [Full Text] [PDF] |
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C. Dechow, C. Morath, J. Peters, I. Lehrke, R. Waldherr, V. Haxsen, E. Ritz, and J. Wagner Effects of all-trans retinoic acid on renin-angiotensin system in rats with experimental nephritis Am J Physiol Renal Physiol, November 1, 2001; 281(5): F909 - F919. [Abstract] [Full Text] [PDF] |
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Y.-X. Wang, B. Martin-McNulty, A. D. Freay, D. A. Sukovich, M. Halks-Miller, W.-W. Li, R. Vergona, M. E. Sullivan, J. Morser, W. P. Dole, et al. Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice Am. J. Pathol., October 1, 2001; 159(4): 1455 - 1464. [Abstract] [Full Text] |
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S. Keidar, R. Heinrich, M. Kaplan, T. Hayek, and M. Aviram Angiotensin II Administration to Atherosclerotic Mice Increases Macrophage Uptake of Oxidized LDL: A Possible Role for Interleukin-6 Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1464 - 1469. [Abstract] [Full Text] [PDF] |
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C. U. Chae, R. T. Lee, N. Rifai, and P. M. Ridker Blood Pressure and Inflammation in Apparently Healthy Men Hypertension, September 1, 2001; 38(3): 399 - 403. [Abstract] [Full Text] [PDF] |
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H. D. Intengan and E. L. Schiffrin Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis Hypertension, September 1, 2001; 38(3): 581 - 587. [Abstract] [Full Text] [PDF] |
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P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF] |
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V. J. Dzau Tissue Angiotensin and Pathobiology of Vascular Disease : A Unifying Hypothesis Hypertension, April 1, 2001; 37(4): 1047 - 1052. [Abstract] [Full Text] [PDF] |
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F. C. Luft Workshop: Mechanisms and Cardiovascular Damage in Hypertension Hypertension, February 1, 2001; 37(2): 594 - 598. [Abstract] [Full Text] [PDF] |
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D. Weiss, J. J. Kools, and W. R. Taylor Angiotensin II-Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice Circulation, January 23, 2001; 103(3): 448 - 454. [Abstract] [Full Text] [PDF] |
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R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF] |
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V. J. Thannickal and B. L. Fanburg Reactive oxygen species in cell signaling Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1005 - L1028. [Abstract] [Full Text] [PDF] |
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K. Irani Oxidant Signaling in Vascular Cell Growth, Death, and Survival : A Review of the Roles of Reactive Oxygen Species in Smooth Muscle and Endothelial Cell Mitogenic and Apoptotic Signaling Circ. Res., August 4, 2000; 87(3): 179 - 183. [Abstract] [Full Text] [PDF] |
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F. J. Miller Jr AIF-1 in the Activated Smooth Muscle Cell : Spectator or Participant? Arterioscler Thromb Vasc Biol, July 1, 2000; 20(7): 1701 - 1703. [Full Text] [PDF] |
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B. Williams The renin angiotensin system and cardiovascular disease: hope or hype? Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 142 - 146. [PDF] |
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E. Mervaala, D. N. Muller, J.-K. Park, R. Dechend, F. Schmidt, A. Fiebeler, M. Bieringer, V. Breu, D. Ganten, H. Haller, et al. Cyclosporin A Protects Against Angiotensin II-Induced End-Organ Damage in Double Transgenic Rats Harboring Human Renin and Angiotensinogen Genes Hypertension, January 1, 2000; 35(1): 360 - 366. [Abstract] [Full Text] [PDF] |
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