(Hypertension. 2000;35:68.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Induction of Cyclooxygenase-2 by Angiotensin II in Cultured Rat Vascular Smooth Muscle Cells
From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Tadashi Inagami, PhD, Department of Biochemistry, Vanderbilt University School of Medicine, 663 Light Hall, Nashville, TN 37232-0146. E-mail inagamit{at}ctrvax.vanderbilt.edu
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Abstract |
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Abstract—Angiotensin II (Ang II) stimulates the release of prostaglandins (PGs) in various cells and tissues. Recently, cyclooxygenase-2 (COX-2) emerged as a new key regulator for PG synthesis. In the present study, we investigated whether Ang II regulates COX-2 expression in cultured rat vascular smooth muscle cells (VSMCs). Ang II markedly increased the expression of COX-2 mRNA in a time- and dose-dependent manner. This effect was completely blocked by the Ang II type 1 receptor antagonist losartan but not by the Ang II type 2 receptor antagonist PD123319. The p42/44 mitogen-activated protein kinase (MAPK) kinase-1 inhibitor PD98059 and the p38 MAPK inhibitor SB203580 significantly suppressed Ang II–induced COX-2 mRNA and protein expression. Ang II did not increase transcription of the COX-2 gene, as examined with a COX-2 promoter/luciferase chimeric plasmid construct. Instead, it suppressed the degradation of COX-2 mRNA. PD98059 and SB203580 markedly enhanced the decay of COX-2 mRNA induced by Ang II, implying that p42/44 and p38 MAPK activated by Ang II play a role in the regulation of COX-2 through stabilization of its mRNA. The COX-2–specific inhibitor NS-398 attenuated Ang II–stimulated DNA and protein synthesis, as well as PGE2 production by VSMCs. These results suggest that Ang II regulates COX-2 expression and PG production and modulates cell proliferation through MAPK-mediated signaling pathways in rat VSMCs.
Key Words: angiotensin II • cyclooxygenase 2 • protein kinases • muscle, smooth, vascular
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Introduction |
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Prostaglandins (PGs) are important mediators in the regulation of cardiovascular and renal functions.1 2 The production of PGs is regulated by a variety of hormones, cytokines, and growth factors.1 2 Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system, has been known to stimulate the release of PGs in a variety of cells,3 4 5 6 7 including vascular smooth muscle cells (VSMCs), through the activation of phospholipase A2 (PLA2), a rate-limiting enzyme in PG synthesis that catalyzes the release of arachidonic acid (AA) from phospholipids in membranes.6 Recent studies have shown that cytosolic PLA2 (cPLA2) plays a role in the release of AA induced by Ang II.8 9
Cyclooxygenase (COX), another rate-limiting enzyme of PG synthesis, catalyzes the conversion of AA to PGG2 and further to PGH2. Two forms of COX, COX-1 and COX-2, have been identified.10 11 Although COX-1 is constitutively expressed in most types of cells and is shown not to be regulated in pathophysiological conditions, COX-2 is induced after stimulation by various growth factors and cytokines.10 11 In contrast to PLA2, little is known about the effect of Ang II on COX-2 expression. Recent studies have indicated the possible involvement of mitogen-activated protein kinases (MAPKs) on COX-2 expression induced by growth factors and cytokines.12 13 14 Ang II is known to activate MAPK cascades in VSMCs to regulate cell function, growth, and differentiation.15 16 17 18 19 These findings prompted us to investigate the effect of Ang II on COX-2 expression and a possible mechanism involving MAPK in cultured VSMCs.
Here, we report our new finding that Ang II markedly increases COX-2 mRNA and protein expression and stimulates PG production through a posttranscriptional mechanism via 2 MAPK (p42/44 MAPK and p38 MAPK)-mediated signaling pathways in VSMCs.
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Methods |
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Materials
DMEM, FCS, penicillin, and streptomycin were obtained from Life Technologies, Inc. Ang II, interleukin-1ß (IL-1ß), and actinomycin D were purchased from Sigma Chemical Co. Losartan was a generous gift from DuPont Merck Pharmaceutical Co. PD123319 was purchased from Research Biochemicals, Inc. PD98059, SB203580, and NS-398 were obtained from Calbiochem. Nimesulide was obtained from Cayman Chemical. Anti–COX-2 polyclonal antibodies were from Oxford Biomedical Research, Inc. Polyclonal antibodies to Thr202- and Tyr204-phosphorylated p42/44 MAPK and to Thr180- and Tyr182-phosphorylated p38 MAPK were purchased from New England Biolabs. Radioisotopes were purchased from New England Nuclear Research Products. All other reagents were of analytical grade.
Cell Culture
VSMCs were prepared from the thoracic aorta of 12-week-old
Sprague-Dawley rats (Charles River Breeding Laboratories) according to
the explant method and cultured in DMEM containing 10% FCS, 100 mU/mL
penicillin, and 100 mU/mL streptomycin as described
previously.16 Cells (passages 3 to 15) at 
90%
confluence in culture dishes were made quiescent through incubation
with serum-free DMEM for 3 days before the experiments.
Preparation of cDNA Probes for COX-1 and COX-2
The cDNA probes for rat COX-1 and COX-2 were prepared through
reverse-transcription polymerase chain reaction (RT-PCR). The primer
sets for COX-1 were 5'-GAG GAT GTC ATC AAG GAG TCC-3' (sense) and
5'-GAC ATA GGG GCA GGT CTT GGT-3' (antisense), and for COX-2, the sets
were 5'-TTC ACC AGA CAG ATT GCT GGC-3' (sense) and 5'-AGT CTG GAG TGG
GAG GCA CTT G-3' (antisense).20 The first-strand cDNA was
synthesized from rat VSMC total RNA with the use of SuperScript II
(Life Technologies, Inc.). Thirty cycles of PCR were performed, with
each cycle consisting of denaturation at 94°C for 1 minute, annealing
at 58°C for 1 minute, and extension at 72°C for 2 minutes. PCR
products with expected sizes for COX-1 (390 bp) and COX-2 (530 bp)
were subcloned to the pGEM-T Easy vector (Promega) according to the T/A
cloning method. The nucleotide sequences of the subcloned
cDNA were confirmed through the dideoxy method with the use of a
SequiTherm EXELTM II DNA sequence kit (Epicentre Technologies) to
coincide with those of rat COX-1 and COX-2 as reported
previously.20
RNA Preparation and Northern Blot Analysis
RNA preparation and Northern blot analysis were
performed essentially as described previously.21 In brief,
total RNA (10 µg) extracted through a single-step
method22 was size-separated with electrophoresis onto a
1% agarose/1% formaldehyde gel and transferred to a
Hybond-N+ membrane (Amersham). Rat COX-1, COX-2,
or GAPDH cDNA was labeled with [
-32P]dATP
with the use of a Prime-It random primer labeling kit (Stratagene) and
used as a probe.
Immunoblotting
Immunoblotting was performed essentially as
described previously.21 In brief, VSMCs grown on 6-well
plates (Falcon Labware) were stimulated with agonists for specified
durations. Cellular lysate was subjected to SDS-PAGE. Proteins in the
gel were transferred to a Hybond ECL nitrocellulose membrane (Amersham)
through electroblotting. The membrane was treated with indicated rabbit
polyclonal antibodies. After incubation with secondary anti-rabbit
horseradish peroxidase–conjugated antibodies, signals were visualized
with an enhanced chemiluminescence detection system (ECL Kit;
Amersham).
Measurement of COX-2 Promoter Activity
High-molecular-weight genomic DNA was purified from cultured rat
VSMCs. The 2.7- and 0.5-kb upstream regions of the rat COX-2 promoter
were amplified through PCR with the use of a
Pfu/Taq polymerase (Boehringer Mannheim).
The primer sets used were 5'-GGG GTA CCG CAG AAG AGG GCG GTA AAA CTC-3'
(sense for 2.7 kb upstream), 5'-GGG GTA CCA GAG CAG CAA GCA CGT CAG
ACT-3' (sense for 0.5 kb upstream), and 5'-CCT AGC TAG CAG CTC TCC GCT
CAG TTT GAC AA-3' (antisense).23 After digestion with
KpnI and NheI, the PCR products were
subcloned into the pGL3 Basic luciferase plasmid (Promega). Sequence
validity was determined as described earlier. For transient
transfection, cells were seeded onto 12-well plates
(5x104/well) 24 hours before cotransfection with
1.0 µg of the COX-2 promoter/pGL3 Basic chimeric plasmid construct,
which expresses firefly luciferase, and 0.02 µg of the pRL-TK plasmid
(Promega), which expresses renilla luciferase, with the use of
Superfect (Qiagen). Transfected cells were cultured for 12 hours in
medium containing 10% FCS, starved of serum for 48 hours, and then
stimulated with IL-1ß (1 ng/mL) or Ang II
(10-7 mol/L) for 24 hours. The cells were washed
with PBS and lysed with passive lysis buffer (Promega). Then, 10 µL
of the lysate was used for both the firefly and renilla luciferase
assays. Luciferase activity was measured with the use of a luminometer.
Firefly luciferase values were standardized to renilla values.
Measurement of PGE2
After stimulation for a specified duration, the culture medium
was collected and centrifuged at 12 000 rpm for 5 minutes.
PGE2 was measured with an ELISA kit
(Cayman Chemical) according to the manufacturer’s instructions.
Protein content was measured with a BCA protein assay kit (Pierce
Chemical Co).
[methyl-3H]Thymidine and
[3H]Leucine Incorporation
After serum starvation for 48 hours, cells in 24-well plates
were stimulated with Ang II for 24 hours.
[methyl-3H]Thymidine (1
µCi/mL) or [3H]leucine (2 µCi/mL) was added
for the last 6 or 24 hours, respectively. Cells were washed twice with
PBS, followed by treatment with 5% trichloroacetic acid for 30 minutes
at 4°C to precipitate proteins. Trichloroacetic acid–precipitable
radioactivity was counted in a scintillation counter.
Statistical Analysis
Data are expressed as mean±SEM. Statistical analyses
were performed with the paired Student’s t test or ANOVA
followed by Fisher’s protected least significant difference test.
Significance was accepted at P<0.05.
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Results |
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Induction of COX-2 mRNA by Ang II
The basal level of COX-2 mRNA (4.1 kb) was low in quiescent rat VSMCs. Stimulation with Ang II (10-7 mol/L) significantly increased COX-2 mRNA expression, which was observed as early as 15 minutes after Ang II addition and reached a peak (9-fold increase) at 1 hour, gradually decreasing to the basal level over 24 hours. The expression level of COX-1 mRNA (3.0 kb) did not change during the stimulation with Ang II (Figure 1A).
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As shown in Figure 1B, the induction of COX-2 mRNA by Ang II was dose dependent. Losartan, an Ang II type 1 (AT1) receptor–specific antagonist, abolished the COX-2 mRNA induction, but PD123319, an Ang II type 2 (AT2) receptor–specific antagonist, did not alter the COX-2 mRNA level. To exclude the possibility that this induction was due to autocrine/paracrine factors released by Ang II, we examined the effect on fresh VSMCs of conditioned medium, in which VSMCs were previously incubated with 10-7 mol/L Ang II for 1 hour. In the presence of losartan (because Ang II remained), the conditioned medium did not increase COX-2 mRNA.
To examine whether the increase in COX-2 mRNA correlated with the protein expression, we studied COX-2 protein expression through the use of immunoblotting analysis. As shown in Figure 1C, the level of COX-2 protein (70 kDa) increased time-dependently, peaking at 4 hours.
Involvement of MAPKs in Induction of COX-2 Expression by Ang
II
To clarify the cellular mechanism by which Ang II induces COX-2
expression, we investigated the possible involvement of MAPK cascades
because we observed the phosphorylation of p42/44 and
p38 MAPKs by Ang II in cultured rat VSMCs (Figure 2A). The p42/44 MAPK kinase
inhibitor PD98059 significantly decreased the COX-2 mRNA
level. The p38 MAPK inhibitor SB203580 also substantially
decreased the COX-2 mRNA level. Cotreatment with PD98059 and SB203580
almost completely abolished the COX-2 mRNA upregulation by Ang II
(Figure 2B), indicating an additive effect of p42/44 MAPK and
p38 MAPK.
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Like COX-2 mRNA, the COX-2 protein expression level stimulated by Ang II was significantly attenuated by PD98059 or SB203580. Combined treatment with PD98059 and SB203580 completely abolished the Ang II–dependent COX-2 protein expression (Figure 2C), again supporting an additive contribution of p42/44 MAPK and p38 MAPK.
Effect of Ang II on COX-2 Transcription Activity
To test whether the increase in COX-2 mRNA by Ang II could be due
to increased transcription, we made 2 COX-2 promoter/luciferase
chimeric plasmid constructs and examined the effect of Ang II on COX-2
promoter activity. IL-1ß, a stimulator of transcription of the COX-2
gene, increased the transcriptional activity of the COX-2 promoter,
whereas Ang II did not increase the transcriptional activity of the
COX-2 promoter (firefly luciferase activity values standardized against
the renilla enzyme were 10.4±0.4 [without stimulation], 23.9±1.3
[with IL-1ß], and 10.7±0.6 [with Ang II] for the 2.7-kb
COX-2 promoter/luciferase plasmid construct and 9.1±0.1 [without
stimulation], 25.5±1.8 [with IL-1ß], and 9.7±0.4 [with Ang II]
for the 0.5-kb COX-2 promoter/luciferase plasmid construct).
Effect of MAPKs on Ang II–Induced COX-2 mRNA Stability
Because Ang II did not stimulate the transcriptional activity of
the COX-2 gene, we investigated an alternative hypothesis that the Ang
II–dependent increase in the COX-2 mRNA level was due to the
stabilization of the mRNA through MAPK activation. After stimulation of
VSMCs with Ang II for 1 hour to allow accumulation of COX-2 mRNA, the
cells were treated with actinomycin D in the presence or absence of the
inhibitor (PD98059 or SB203580) to block further
transcription. In the absence of the inhibitor, the mRNA
decay was gradual, whereas the addition of inhibitors
accelerated the decay of COX-2 mRNA (Figure 3), suggesting that the stimulation of
p42/44 or p38 MAPK activity by Ang II stabilizes the COX-2 mRNA, which
in turn increases overall COX-2 protein expression.
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),
PD98059 (25 µmol/L, 
), or SB203580 (10 µmol/L, 
)
was added to the cells for times indicated. COX-2 and GAPDH mRNAs were
analyzed by Northern blot analysis. A, A
representative autoradiograph is shown. B, COX-2 and
GAPDH mRNAs were quantified by densitometry. Results are expressed as
percentages of ratio of COX-2 mRNA/GAPDH mRNA after 1 hour of
stimulation with 10-7 mol/L Ang II (mean±SEM, n=3).
*P<0.01 vs vehicle.
Effect of COX-2 Inhibitor on PGE2
Production
As shown in Figure 4, Ang II
stimulated the release of PGE2 from cultured rat
VSMCs. Pretreatment with the COX-2 inhibitor NS-398
dose-dependently suppressed the Ang II–stimulated
PGE2 production. NS-398 (10
µmol/L) almost completely suppressed PGE2
production to a basal level. NS-398 alone did not affect the
basal PGE2 production. These results
indicates that COX-2 activated by Ang II is the rate-limiting
step for PGE2 synthesis.
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Effect of COX-2 Inhibitor on Ang II–Stimulated DNA and
Protein Synthesis
Ang II induced a 2.3-fold increase in
[methyl-3H]thymidine
incorporation by rat VSMCs over 24 hours. The Ang II–induced increase
was diminished in the presence of the COX-2 inhibitors
NS-398 or nimesulide (Figure 5A). Ang II
also stimulated [3H]leucine incorporation,
which was partially suppressed by NS-398 or nimesulide (Figure 5B).
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Discussion |
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The results of the present study have clearly demonstrated that Ang II induces COX-2 expression in cultured rat VSMCs, a novel finding that has not been reported previously to our knowledge. Ang II is known to stimulate the production of PGs in VSMCs,3 4 5 mesangial cells,6 endothelial cells,7 and other types of cells. Earlier studies considered that the stimulation was mostly due to PLA2 activation.8 9 The present findings suggest that the stimulation of PG production by Ang II in VSMCs is in part ascribed to the induction of COX-2 expression in addition to the activation of PLA2.
The peak of COX-2 mRNA induction by Ang II was observed at 1 hour. The rapid induction of COX-2 mRNA followed by the increase in protein expression is similar to that observed after treatment with cytokines and growth factors, which is consistent with the concept that COX-2 is an early-immediate gene. The induction of COX-2 by Ang II was completely inhibited by the AT1 receptor antagonist losartan but not by the AT2 receptor antagonist PD123319, suggesting that this effect is transmitted through the AT1 receptor. Because the conditioned medium in which VSMCs were preincubated with Ang II had no effect on COX-2 induction, the possibility of the contribution of other factors released by Ang II seems to be negligible. Mangat et al24 reported that Ang II acting through the AT1 receptor is involved in increased expression of cPLA2 and COX-2 in response to chronic hypercalcemia in rat kidney. On the other hand, Cheng et al25 recently demonstrated that Ang II attenuates COX-2 expression in the macula densa of rat kidney. However, because they investigated the effect of Ang II on COX-2 expression through chronic in vivo study and they did not show the mechanism by which Ang II attenuates COX-2 expression, it is not easy to compare their results with those observed in the present in vitro study. Because PGs produced in the macula densa directly regulate renin production in juxtaglomerular cells,25 Ang II may have an opposite action in macula densa cells.
MAPKs are reportedly involved in the regulation of growth factor– or cytokine-induced expression of COX-2.12 13 14 Given the observation that Ang II activates the MAPK pathways in VSMCs,15 16 17 18 19 MAPKs seemed to be a plausible factor involved in the Ang II–induced COX-2 expression. Although PD98059 or SB203580 alone partially suppressed the Ang II–induced COX-2 mRNA and protein expression, a combination of both almost completely abolished the COX-2 expression. Therefore, the activation of both p42/44 MAPK and p38 MAPK might be required for the full expression of COX-2 induced by Ang II. In our rat VSMCs, Ang II did not show significant activation of c-Jun N-terminal kinase (JNK; data not shown) despite a few reports of JNK activation by Ang II.18 Almost complete suppression of COX-2 expression through the simultaneous inhibition of both p42/44 MAPK and p38 MAPK supports the conclusion that the role of JNK is minor, if any.
Upregulation of mRNA is due to an increased transcriptional activity or decreased mRNA degradation. Through measurement of the promoter activity with the use of a COX-2 promoter/luciferase chimeric plasmid construct transfected into VSMCs, our present results show that IL-1ß significantly increased the transcriptional activity of the COX-2 gene but that Ang II did not increase the activity. Therefore, it seems unlikely that an increase in transcription is the mechanism of the induction of COX-2 by Ang II. Indeed, the 3'-untranslated region of rat COX-2 mRNA contains 22 copies of the AUUUA motif,26 which is known to be a selective mRNA-destabilizing sequence.27 Interestingly, our results indicate that the suppression of the mRNA degradation by Ang II in VSMCs is the mechanism for stimulation of COX-2 expression and that the suppression of the mRNA decay is mediated by the joint action of p42/44 MAPK and p38 MAPK, which is in agreement with observations of COX-2 stimulation by lipopolysaccharide,28 IL-1,29 or Ha-ras oncogene30 in other types of cells. Although the detailed mechanism by which MAPKs stabilize COX-2 mRNA is unclear, it is reasonable to speculate that the activation of these MAPKs by Ang II may induce factors that stabilize COX-2 mRNA or inhibit factors that destabilize the mRNA, thereby markedly enhancing the Ang II–stimulated COX-2 mRNA expression. Further studies on the involvement of p42/44 MAPK and p38 MAPK in the stabilization of COX-2 mRNA are required.
NS-398, a selective COX-2 inhibitor, suppressed the Ang II–stimulated PGE2 production dose-dependently to the basal level, without affecting the basal production of PGE2, which is considered to be a product derived mostly through COX-1 activity. Therefore, NS-398 inhibited mainly the Ang II–induced COX-2 activity, which resulted in a reduction in PGE2 production. The inhibition of COX-2 activity with a specific inhibitor, such as NS-398 or nimesulide, significantly attenuated Ang II–stimulated DNA and protein synthesis in VSMCs. The biological significance of COX-2 activation by Ang II in VSMCs remains to be established. The detailed mechanism by which COX-2 inhibitors suppressed the Ang II–stimulated DNA and protein synthesis in rat VSMCs is uncertain, but increased production of PGs have been implicated to take part in modulation of cell proliferation in VSMCs.31 Furthermore, COX-2 expression was shown to increase in rat VSMCs after balloon injury in vivo32 and in response to serum or growth factors.32 33 The overexpression of COX-2 in epithelial cells inhibits apoptosis.34 Given these findings, a subset of COX-2 products stimulated by Ang II may play a role in the proliferation of VSMCs under circumstances in which the renin-angiotensin system is involved, such as in vascular remodeling.
In summary, the results of the present study demonstrate that Ang II regulates COX-2 expression and PG production through p42/44 MAPK and p38 MAPK pathways in rat VSMCs. Ang II–induced COX-2 activation may play a significant role in the mediation of cell growth and the proliferation of VSMCs.
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants HL-58205 and DK-20593. We thank Trinita Fitzgerald, Edward Price, and Tina Stack for their valuable assistance. We also thank Masaaki Tamura (Department of Biochemistry, Vanderbilt University) and Pamela J. Tamura (Department of Chemistry, Vanderbilt University) for critical reading and constructive comments during preparation of this manuscript.
Received June 3, 1999; first decision June 29, 1999; accepted August 25, 1999.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Campbell WB, Halushka PV. Lipid-derived autacoids: eicosanoids and platelet-activating factor. In: Hardman JG, Limbird LE, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:601–616.
2.
Smith WL. Prostanoid biosynthesis and mechanisms of
action. Am J Physiol. 1992;263:F181–F191.
3.
Alexander RW, Gimbrone MA Jr. Stimulation of
prostaglandin E synthesis in cultured human umbilical vein
smooth muscle cells. Proc Natl Acad Sci U S A. 1976;73:1617–1620.
4.
Vallotton MB, Gerber-Wicht C, Dolci W, Wüthrich
RP. Interaction of vasopressin and angiotensin II in
stimulation of prostacyclin synthesis in vascular smooth muscle cells.
Am J Physiol. 1989;257:E617–E624.
5. Catalioto R-M, Renzetti AR, Criscuoli M, Morbidelli L, Subissi A. Role of calcium in angiotensin II-induced prostaglandin release and DNA synthesis in rat vascular smooth muscle cells. J Cardiovasc Pharmacol. 1996;27:195–200.[Medline] [Order article via Infotrieve]
6.
Schlondorff D, DeCandido S, Satriano JA.
Angiotensin II stimulates phospholipases C and A2 in
cultured rat mesangial cells. Am J Physiol. 1987;253:C113–C120.
7.
Gimbrone MA Jr, Alexander RW. Angiotensin
II stimulation of prostaglandin production in
cultured human vascular endothelium.
Science. 1975;189:219–220.
8. Rao GN, Lassegue B, Alexander RW, Griendling KK. Angiotensin II stimulates phosphorylation of high-molecular-mass cytosolic phospholipase A2 in vascular smooth-muscle cells. Biochem J. 1994;299:197–201.
9. Freeman EJ, Ruehr ML, Dorman RV. ANG II-induced translocation of cytosolic PLA2 to the nucleus in vascular smooth muscle cells. Am J Physiol. 1998;274:C282–C288.
10. Vane JR, Bakhle Y, Botting R. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998;38:97–120.[Medline] [Order article via Infotrieve]
11.
DuBois RN, Abramson SB, Crofford L, Gupta RA, Simon LS,
Van De Putte LBA, Lipsky PE. Cyclooxygenase in
biology and disease. FASEB J. 1998;12:1063–1073.
12. Bornfeldt KE, Campbell JS, Koyama H, Argast GM, Leslie CC, Raines EW, Krebs EG, Ross R. The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells: dependence on the availability of downstream targets. J Clin Invest. 1997;100:875–885.[Medline] [Order article via Infotrieve]
13.
Guan Z, Buckman SY, Miller BW, Springer LD, Morrison
AR. Interleukin-1ß-induced cyclooxygenase-2
expression requires activation of both c-Jun NH2-terminal kinase and
p38 MAPK signal pathways in rat renal mesangial cells.
J Biol Chem. 1998;273:28670–28676.
14. LaPointe MC, Isenovic E. Interleukin-1ß regulation of inducible nitric oxide synthase and cyclooxygenase-2 involves the p42/44 and p38 MAPK signaling pathways in cardiac myocytes. Hypertension. 1999;33(suppl II):II-276–II-282.
15. Duff JL, Berk BC, Corson MA. Angiotensin II stimulates the pp44 and pp42 mitogen-activated protein kinases in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun. 1992;188:257–264.[Medline] [Order article via Infotrieve]
16.
Eguchi S, Matsumoto T, Motley ED, Utsunomiya H, Inagami
T. Identification of an essential signaling cascade for
mitogen-activated protein kinase activation by
angiotensin II in cultured rat vascular smooth muscle
cells. J Biol Chem. 1996;271:14169–14175.
17.
Ushio-Fukai M, Alexander RW, Akers M, Griendling KK.
p38 mitogen-activated protein kinase is a critical component of
the redox-sensitive signaling pathways activated by
angiotensin II. J Biol Chem. 1998;273:15022–15029.
18.
Schmitz U, Ishida T, Ishida M, Surapisitchat J, Hasham
MI, Pelech S, Berk BC. Angiotensin II stimulates
p21-activated kinase in vascular smooth muscle cells: role in
activation of JNK. Circ Res. 1998;82:1272–1278.
19. Takahashi E, Berk BC. MAP kinases and vascular smooth muscle function. Acta Physiol Scand. 1998;164:611–621.[Medline] [Order article via Infotrieve]
20. Feng L, Sun W, Xia Y, Tang WW, Chanmugam P, Soyoola E, Wilson CB, Hwang D. Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression. Arch Biochem Biophys. 1993;307:361–368.[Medline] [Order article via Infotrieve]
21. Yamakawa T, Eguchi S, Yamakawa Y, Motley ED, Numaguchi K, Utsunomiya H, Inagami T. Lysophosphatidylcholine stimulates MAP kinase activity in rat vascular smooth muscle cells. Hypertension. 1998;31(suppl II):II-248–II-253.
22. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–159.[Medline] [Order article via Infotrieve]
23.
Sirois J, Levy LO, Simmons DL, Richards JS.
Characterization and hormonal regulation of the promoter of the rat
prostaglandin endoperoxide synthase 2 gene
in granulosa cells. J Biol Chem. 1993;268:12199–12206.
24. Mangat H, Peterson LN, Burns KD. Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats: role of angiotensin II AT1 receptors. J Clin Invest. 1997;100:1941–1950.[Medline] [Order article via Infotrieve]
25. Cheng H-F, Wang J-L, Zhang M-Z, Miyazaki Y, Ichikawa I, McKanna JA, Harris RC. Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. J Clin Invest. 1999;103:953–961.[Medline] [Order article via Infotrieve]
26. Ristimäki A, Narko K, Hla T. Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: evidence for post-transcriptional regulation. Biochem J. 1996;318:325–331.
27. Shaw G, Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986;46:659–667.[Medline] [Order article via Infotrieve]
28.
Dean JLE, Brook M, Clark AR, Saklatvala J. p38
mitogen-activated protein kinase regulates
cyclooxygenase-2 mRNA stability and transcription
in lipopolysaccharide-treated human monocytes. J
Biol Chem. 1999;274:264–269.
29. Ridley SH, Dean JLE, Sarsfield SJ, Brook M, Clark AR, Saklatvala J. p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA. FEBS Lett. 1998;439:75–80.[Medline] [Order article via Infotrieve]
30.
Sheng H, Williams CS, Shao J, Liang P, DuBois RN,
Beauchamp RD. Induction of cyclooxygenase-2 by
activated Ha-ras oncogene in Rat-1 fibroblasts and
the role of mitogen-activated protein kinase pathway.
J Biol Chem. 1998;273:22120–22127.
31.
Pomerantz KB, Hajjar DP. Eicosanoids in regulation of
arterial smooth muscle cell phenotype,
proliferative capacity, and cholesterol
metabolism.
Arteriosclerosis. 1989;9:413–429.
32.
Pritchard KA Jr, O’Banion MK, Miano JM, Vlasic N,
Bhatia UG, Young DA, Stemerman MB. Induction of
cyclooxygenase-2 in rat vascular smooth muscle
cells in vitro and in vivo. J Biol Chem. 1994;269:8504–8509.
33.
Rimarachin JA, Jacobson JA, Szabo P, Maclouf J,
Creminon C, Weksler BB. Regulation of
cyclooxygenase-2 expression in aortic smooth muscle
cells. Arterioscler Thromb. 1994;14:1021–1031.
34. Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995;83:493–501.[Medline] [Order article via Infotrieve]
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 A. J. Casal, S. Ryser, A. M. Capponi, and C. F. Wang-Buholzer Angiotensin II-Induced Mitogen-Activated Protein Kinase Phosphatase-1 Expression in Bovine Adrenal Glomerulosa Cells: Implications in Mineralocorticoid Biosynthesis Endocrinology, November 1, 2007; 148(11): 5573 - 5581. [Abstract] [Full Text] [PDF]
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Y. Alvarez, J. V. Perez-Giron, R. Hernanz, A. M. Briones, A. Garcia-Redondo, A. Beltran, M. J. Alonso, and M. Salaices Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 381 - 388. [Abstract] [Full Text] [PDF]
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 T. A. Morinelli, J. R. Raymond, A. Baldys, Q. Yang, M.-h. Lee, L. Luttrell, and M. E. Ullian Identification of a putative nuclear localization sequence within ANG II AT1A receptor associated with nuclear activation Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1398 - C1408. [Abstract] [Full Text] [PDF]
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 A. L. Opay, C. R. Mouton, J. J. Mullins, and K. D. Mitchell Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension Am J Physiol Renal Physiol, September 1, 2006; 291(3): F612 - F618. [Abstract] [Full Text] [PDF]
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 Z. Qi, H. Cai, J. D. Morrow, and M. D. Breyer Differentiation of Cyclooxygenase 1- and 2-Derived Prostanoids in Mouse Kidney and Aorta Hypertension, August 1, 2006; 48(2): 323 - 328. [Abstract] [Full Text] [PDF]
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 V. L. King, D. B. Trivedi, J. M. Gitlin, and C. D. Loftin Selective Cyclooxygenase-2 Inhibition With Celecoxib Decreases Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1137 - 1143. [Abstract] [Full Text] [PDF]
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 A Mezzetti Pharmacological modulation of plaque instability Lupus, September 1, 2005; 14(9): 769 - 772. [Abstract] [PDF]
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 Z. Guo, W. Su, S. Allen, H. Pang, A. Daugherty, E. Smart, and M. C. Gong COX-2 Up-regulation and vascular smooth muscle contractile hyperreactivity in spontaneous diabetic db/db mice Cardiovasc Res, September 1, 2005; 67(4): 723 - 735. [Abstract] [Full Text] [PDF]
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 R. Pullmann Jr., M. Juhaszova, I. L. de Silanes, T. Kawai, K. Mazan-Mamczarz, M. K. Halushka, and M. Gorospe Enhanced Proliferation of Cultured Human Vascular Smooth Muscle Cells Linked to Increased Function of RNA-binding Protein HuR J. Biol. Chem., June 17, 2005; 280(24): 22819 - 22826. [Abstract] [Full Text] [PDF]
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 K. K. K. Sheares, T. K. Jeffery, L. Long, X. Yang, and N. W. Morrell Differential effects of TGF-{beta}1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, November 1, 2004; 287(5): L919 - L927. [Abstract] [Full Text] [PDF]
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 I. Drenjancevic-Peric and J. H. Lombard Introgression of chromosome 13 in Dahl salt-sensitive genetic background restores cerebral vascular relaxation Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H957 - H962. [Abstract] [Full Text] [PDF]
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 K. L. Therland, J. Stubbe, H. C. Thiesson, P. D. Ottosen, S. Walter, G. L. Sorensen, O. Skott, and B. L. Jensen Cycloxygenase-2 Is Expressed in Vasculature of Normal and Ischemic Adult Human Kidney and Is Colocalized with Vascular Prostaglandin E2 EP4 Receptors J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1189 - 1198. [Abstract] [Full Text] [PDF]
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 F. Cipollone, M. Fazia, A. Iezzi, B. Pini, C. Cuccurullo, M. Zucchelli, D. de Cesare, S. Ucchino, F. Spigonardo, M. De Luca, et al. Blockade of the Angiotensin II Type 1 Receptor Stabilizes Atherosclerotic Plaques in Humans by Inhibiting Prostaglandin E2-Dependent Matrix Metalloproteinase Activity Circulation, March 30, 2004; 109(12): 1482 - 1488. [Abstract] [Full Text] [PDF]
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F. Cipollone, B. Rocca, and C. Patrono Cyclooxygenase-2 Expression and Inhibition in Atherothrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 246 - 255. [Abstract] [Full Text]
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T. Suganami, K. Mori, I. Tanaka, M. Mukoyama, A. Sugawara, H. Makino, S. Muro, K. Yahata, S. Ohuchida, T. Maruyama, et al. Role of Prostaglandin E Receptor EP1 Subtype in the Development of Renal Injury in Genetically Hypertensive Rats Hypertension, December 1, 2003; 42(6): 1183 - 1190. [Abstract] [Full Text] [PDF]
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M. A Frias, F. Dubouloz, M. C Rebsamen, and U. Lang Prostacyclin production in rat aortic smooth muscle cells: role of protein kinase C, phospholipase D and cyclooxygenase-2 expression Cardiovasc Res, November 1, 2003; 60(2): 438 - 446. [Abstract] [Full Text] [PDF]
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D. Chen, E. V. Balyakina, M. Lawrence, B. W. Christman, and B. Meyrick Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells Am J Physiol Lung Cell Mol Physiol, April 1, 2003; 284(4): L614 - L621. [Abstract] [Full Text] [PDF]
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 T. G. Tessner, F. Muhale, S. Schloemann, S. M. Cohn, A. Morrison, and W. F. Stenson Basic fibroblast growth factor upregulates cyclooxygenase-2 in I407 cells through p38 MAP kinase Am J Physiol Gastrointest Liver Physiol, February 1, 2003; 284(2): G269 - G279. [Abstract] [Full Text] [PDF]
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 X. Yang, K. K. K. Sheares, N. Davie, P. D. Upton, G. W. Taylor, J. Horsley, J. Wharton, and N. W. Morrell Hypoxic Induction of Cox-2 Regulates Proliferation of Human Pulmonary Artery Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 688 - 696. [Abstract] [Full Text] [PDF]
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Z.-W. Hu, R. Kerb, X.-Y. Shi, T. Wei-Lavery, and B. B. Hoffman Angiotensin II Increases Expression of Cyclooxygenase-2: Implications for the Function of Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 563 - 573. [Abstract] [Full Text] [PDF]
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Y. Mukai, H. Shimokawa, M. Higashi, K. Morikawa, T. Matoba, J. Hiroki, I. Kunihiro, H. M.A. Talukder, and A. Takeshita Inhibition of Renin-Angiotensin System Ameliorates Endothelial Dysfunction Associated With Aging in Rats Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): 1445 - 1450. [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. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]
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M. Mendez and M. C. LaPointe Trophic Effects of the Cyclooxygenase-2 Product Prostaglandin E2 in Cardiac Myocytes Hypertension, February 1, 2002; 39(2): 382 - 388. [Abstract] [Full Text] [PDF]
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C. M. Reynolds, S. Eguchi, G. D. Frank, and E. D. Motley Signaling Mechanisms of Heparin-Binding Epidermal Growth Factor-Like Growth Factor in Vascular Smooth Muscle Cells Hypertension, February 1, 2002; 39(2): 525 - 529. [Abstract] [Full Text] [PDF]
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 J. Schnermann Cyclooxygenase-2 and macula densa control of renin secretion Nephrol. Dial. Transplant., September 1, 2001; 16(9): 1735 - 1738. [Full Text] [PDF]
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J. Schwobel, T. Fischer, B. Lanz, and M. Mohaupt Angiotensin II receptor subtypes determine induced NO production in rat glomerular mesangial cells Am J Physiol Renal Physiol, December 1, 2000; 279(6): F1092 - F1100. [Abstract] [Full Text] [PDF]
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T. Yang, Y. Endo, Y. G. Huang, A. Smart, J. P. Briggs, and J. Schnermann Renin expression in COX-2-knockout mice on normal or low-salt diets Am J Physiol Renal Physiol, November 1, 2000; 279(5): F819 - F825. [Abstract] [Full Text] [PDF]
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F. Stanke-Labesque, P. Devillier, P. Bedouch, J. L. Cracowski, O. Chavanon, and G. Bessard Angiotensin II-induced contractions in human internal mammary artery: effects of cyclooxygenase and lipoxygenase inhibition Cardiovasc Res, August 1, 2000; 47(2): 376 - 383. [Abstract] [Full Text] [PDF]
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J. Hernandez, H. Astudillo, and B. Escalante Angiotensin II stimulates cyclooxygenase-2 mRNA expression in renal tissue from rats with kidney failure Am J Physiol Renal Physiol, April 1, 2002; 282(4): F592 - F598. [Abstract] [Full Text] [PDF]
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C. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]
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