© 1999 American Heart Association, Inc.
Vascular Biology |
Angiotensin Induces Inflammatory Activation of Human Vascular Smooth Muscle Cells
Presented in part at the annual spring meeting of the German Society of Heart Research, Mannheim, Germany, April 3–5, 1997, and at the 70th Scientific Sessions of the American Heart Association, Orlando, Florida, November 9–12, 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
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Abstract |
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Abstract—Multiple data suggest that the renin-angiotensin system contributes to the pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin system can only in part be explained by the influence of its effector angiotensin II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic activity. Because chronic inflammation of the vessel wall is a hallmark of atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin. Inflammatory activation was assessed by determination of interleukin-6 (IL-6) release into the culture medium, detection of IL-6 mRNA by RT-PCR, and demonstration of activation of nuclear factor-
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 II–induced 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
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Introduction |
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Several lines of evidence suggest a role of the renin-angiotensin system in the pathogenesis of atherosclerosis. Immunohistochemical studies demonstrated increased accumulation of angiotensin-converting enzyme (ACE) in human atheroma.1 Molecular genetic studies showed an association of variants in the genes for ACE and angiotensinogen with an increased risk for myocardial infarction or coronary heart disease,2 3 although conflicting data exist.4 Prospective clinical investigations showed an association between plasma renin activity and the risk of myocardial infarction and ischemic heart disease.5 6 7 Large clinical trials investigating the effect of ACE inhibitors on survival after myocardial infarction showed convincingly a reduction of reinfarction rate mostly independent from blood pressure lowering.8 9 10 In animals, ACE inhibitors had a protective effect against atherosclerosis.11
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.
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Methods |
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Cell Preparation and Culture
Vascular SMCs were cultured by explant outgrowth from unused portions of human saphenous veins harvested for coronary bypass surgery. Cells were grown in DMEM (Eurobio) supplemented with 10% (vol/vol) FCS (Eurobio), 100 U/mL penicillin, 100 µg/mL streptomycin, 1.25 µg/mL amphotericin B, and 2 mmol/L L-glutamine. The cells exhibited the typical "hill and valley" growth morphology of SMCs and many reacted with the monoclonal antibody HHF-35 that selectively recognizes muscle forms of actin but does not react with endothelial cells or fibroblasts.29 Cells from passages 2 to 5 were used for the experiments after being growth-arrested for 2 days in serum-free insulin–transferrin medium consisting of DMEM and Ham's F12 (1:1, vol/vol; Eurobio) supplemented with 1 µmol/L insulin and 5 µg/mL transferrin.30 Fresh insulin–transferrin medium was used for the experiments with or without addition of stimuli.
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
insulin–transferrin 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-6–specific
primers (5'-ATGAACTCCTTCTCCACAAGCGC-3' and
5'-GAAGAGCCCTCAGGCTGGACTG-3') and
glyceraldehyde-3-phosphate dehydrogenase–specific
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-B–bound 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.
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Results |
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Angiotensin II Induces Cytokine Release From Vascular SMCs
We used measurement of IL-6 in cell supernatants to gauge the ability of angiotensin II to induce cytokine production, because this member of the cytokine family is rapidly secreted on its induction.22 Angiotensin II caused concentration- and time-dependent IL-6 release from SMCs from 1 nmol/L to 1 µmol/L (Figure 1
). At 1 µmol/L
angiotensin II, IL-6 release ranged between 61% and 79%
of the release obtained with a maximally effective positive control
stimulus, TNF (20 ng/mL). Four experiments with cells from different
donors gave similar results.
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Angiotensin II–Induced 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 II–stimulated IL-6 release from SMCs
(Figure 2). This finding demonstrates
both specificity of the angiotensin II effect and
involvement of the type 1 receptor.
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Angiotensin I Stimulates IL-6 Release by SMCs via an
Angiotensin-Converting Enzyme–Dependent 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 concentration–response curve shifted to the right compared with
angiotensin II. Angiotensin I–induced 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
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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).
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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).
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PDTC Inhibits Angiotensin II–Induced 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 II–induced 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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The present data demonstrate the potential of angiotensin to induce inflammatory activation and cytokine production in human vascular SMCs. Angiotensin II dose-dependently increased IL-6 release by SMCs via the angiotensin type 1 receptor. Moreover, angiotensin I also increased IL-6 production by SMCs via an ACE-dependent mechanism. Stimulation of SMCs by angiotensin II resulted in increased accumulation of IL-6 mRNA, suggesting interaction of angiotensin with IL-6 release at the pretranslational level. Finally, angiotensin II potently activated NF-
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 II–induced IL-6 release by the radical
scavenger PDTC. This finding is compatible with the hypothesis that
reactive oxygen intermediates participate in angiotensin
II–stimulated 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.
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Acknowledgments |
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This study was supported by grants from the Deutsche Forschungs–gemeinschaft (Kr 1363/1-3) and the Medical Faculty of the University of Heidelberg to Dr Kranzhöfer and from the National Heart, Lung, and Blood Institute to Dr Libby (HL-48743). We thank our colleagues from the Department of Cardiac Surgery, University of Heidelberg, for supplying us with human saphenous veins.
Received July 29, 1998; accepted November 26, 1998.
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