© 1999 American Heart Association, Inc.
Vascular Biology |
Platelet-Derived Growth Factor Stimulates Heme Oxygenase-1 Gene Expression and Carbon Monoxide Production in Vascular Smooth Muscle Cells
From the Houston VA Medical Center (W.D., K.J.P., A.I.S.) and the Departments of Medicine and Pharmacology (W.D.), Baylor College of Medicine, Houston, Tex.
Correspondence to William Durante, PhD, Houston VA Medical Center, Building 109, Room 130, 2002 Holcombe Blvd, Houston, TX 77030. E-mail wdurante{at}bcm.tmc.edu
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Abstract |
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Abstract—Recent studies indicate that vascular smooth muscle cells (VSMCs) generate CO from the degradation of heme by the enzyme heme oxygenase-1 (HO-1). Because platelet-derived growth factor (PDGF) modulates various responses of VSMCs, we examined whether this peptide regulates the expression of HO-1 and the production of CO by rat aortic SMCs. Treatment of SMCs with PDGF resulted in a time- and concentration-dependent increase in the levels of HO-1 mRNA and protein. Both actinomycin D and cycloheximide blocked PDGF-stimulated HO-1 mRNA and protein. In addition, PDGF stimulated the production of reactive oxygen species by SMCs. Both the PDGF-mediated generation of reactive oxygen species and the induction of HO-1 protein was inhibited by the antioxidant N-acetyl-L-cysteine. Incubation of platelets with PDGF-treated SMCs resulted in a significant increase in platelet cGMP concentration that was reversed by treatment of SMCs with the HO-1 inhibitor tin protoporphyrin-IX or by addition of the CO scavenger hemoglobin to platelets. In contrast, the nitric oxide inhibitor methyl-L-arginine did not block the stimulatory effect of PDGF-treated SMCs on platelet cGMP. Finally, incubation of SMCs with the releasate from collagen-activated platelets induced HO-1 protein expression that was blocked by a neutralizing antibody to PDGF. These results demonstrate that either administered exogenously or released by platelets, PDGF stimulates HO-1 gene expression and CO synthesis in vascular smooth muscle. The ability of PDGF to induce HO-1–catalyzed CO release by VSMCs may represent a novel mechanism by which this growth factor regulates vascular cell and platelet function.
Key Words: platelet-derived growth factor • carbon monoxide • heme oxygenase
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Introduction |
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Heme oxygenase (HO) catalyzes the rate-limiting step in the oxidative degradation of heme to biliverdin, releasing equimolar amounts of carbon monoxide (CO) and iron.1 HO is a ubiquitous protein that exists in at least 3 different isoforms that are products of distinct genes.2 3 The HO-2 isoform is constitutively expressed and is present at high levels in the brain and testes.4 In contrast, the HO-1 isotype is widely distributed and rapidly induced by several oxidants, including superoxide anion, hydrogen peroxide, ultraviolet radiation, and nitric oxide.5 6 7 8 More recently, a third HO protein, HO-3, that is closely related to HO-2 has been identified.9 The induction of HO may provide an important cellular defense mechanism against oxidative injury. HO-1 expression has been shown to be protective against ischemia-reperfusion and free radical damage in a number of tissues.7 10 11 12 These protective effects of HO-1 result from the conversion of pro-oxidant heme to the antioxidant bile pigments biliverdin and bilirubin.13 14 In addition, HO-1 induction is accompanied by increased ferritin activity, which exerts an additional antioxidant effect by chelating free iron.15
More recently, HO-catalyzed CO release has been shown to play a significant physiological role in the circulation.16 Exogenous administration of CO relaxes isolated blood vessels from various vascular sources and animal species.17 18 19 20 Moreover, the administration of inducers of HO-1 causes a marked decrease in blood pressure in hypertensive rats, whereas HO-1 inhibitors increase blood pressure and peripheral resistance, suggesting that endogenous CO subserves a tonic vasodepressor function.21 22 CO also inhibits the synthesis of growth factors from vascular cells and directly blocks smooth muscle cell (SMC) growth, indicating a potentially important antiproliferative role for this gas.23 24 In addition to regulating SMC function, CO modulates platelet reactivity. Both exogenously administered and vascular cell–derived CO inhibit platelet aggregation.25 26 All these biological effects of CO are mediated via the activation of soluble guanylate cyclase and the consequent rise in intracellular cGMP levels in target tissues.17 19 24 25 26
Several studies have detected the presence of HO-1 and the release of CO by vascular smooth muscle cells (VSMCs).27 28 29 However, relatively little is known about the regulation of HO-1 gene expression and CO production by physiologically relevant stimuli. Platelet-derived growth factor (PDGF) is a cationic peptide that is secreted by platelets, macrophages, and vascular cells at sites of inflammation and vascular damage.30 It has been implicated in the vascular response to injury and in the pathogenesis of atherosclerosis and hypertension.30 31 32 PDGF modulates numerous SMC responses, including growth, migration, and contraction.30 33 Recently, we found that PDGF also plays an important role in regulating the synthesis of another diatomic signaling gas, NO.34 35 36 Accordingly, the present study examined whether PDGF also regulates the synthesis of CO by VSMCs. We now report that PDGF, either exogenously administered or endogenously generated from activated platelets, induces HO-1 gene expression and CO release in VSMCs. The ability of PDGF to stimulate CO synthesis may provide a novel mechanism by which PDGF regulates SMC function.
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Methods |
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Materials
Fatty acid–free albumin, FCS, L-glutamine, penicillin, streptomycin, elastase, trypsin, collagenase, sodium citrate, sodium acetate, sodium dodecyl sulfate (SDS), trichloroacetic acid (TCA), 3-isobutyl-1-methylxanthine (IBMX), cycloheximide, EDTA, formamide, DTT, formaldehyde, tris(hydroxymethyl)aminomethane (Tris) base, N-acetyl-L-cysteine (NAC), creatine phosphate, creatine phosphokinase, HEPES, TES, sepharose 2B-300, Tween 20, and Eagle’s minimum essential medium (MEM) were from Sigma Chemical Co; guanidine isothiocyanate, sonicated salmon sperm, and CsCl were from GIBCO; PDGF-AB (human recombinant), actinomycin D, ribonuclease A, and ribonuclease T1 were from Boehringer Mannheim; T7 RNA polymerase, RNA molecular weight markers, and antisense GAPDH template were from Ambion; 5,6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA) was from Molecular Probes; anti-PDGF antibody was from Upstate Biotechnology; tin protoporphyrin-IX (SnPP-IX) was from Porphyrin Products; human oxyhemoglobin was from Calzyme Laboratories; polyclonal HO-1 antibody was from StressGen; and [32P]UTP (400 Ci/mmol) was from Amersham.
Cell Culture
SMCs were isolated by elastase and collagenase
digestion of rat thoracic aorta and were characterized according to
morphological and immunological criteria, as previously
described.37 Cells were propagated in MEM containing
Earle’s balanced salts, 5.6 mmol/L glucose, 2 mmol/L
L-glutamine, 20 mmol/L TES-NaOH, 20 mmol/L
HEPES-NaOH, 10% (vol/vol) heat-inactivated FCS, 100 U/mL
penicillin, and 100 U/mL streptomycin. SMCs were passaged twice a week
by harvesting with trypsin/EDTA and seeded into
75-cm2 flasks. For experiments, subcultured
confluent cells between passages 6 and 26 were used.
mRNA Analysis
Total cellular RNA was obtained by the guanidine
isothiocyanate/CsCl procedure, and RNA concentration was determined by
absorbance spectrophotometry at 260 nm.38 HO-1 mRNA levels
were determined by solution hybridization/ribonuclease protection
analysis, as previously described.8 In brief,
total RNA (10 µg) was hybridized with 1x105
cpm [32P]UTP-labeled antisense HO-1 riboprobe
and with antisense GAPDH (316-bp) RNA to control for variations in the
amount of RNA used in each assay. The HO-1 (284-bp) antisense RNA probe
was prepared as described earlier.8 Samples were incubated
in hybridization buffer (65 mmol/L sodium citrate, 200 mmol/L
sodium acetate, 0.5 mmol/L EDTA, and 55% formamide) for 16 hours
at 45°C, followed by digestion with ribonuclease A (4.0 µg/mL) and
ribonuclease T1 (0.2 µg/mL) at room temperature for 30 minutes,
whereas a 10-fold higher concentration of ribonucleases was used for
GAPDH digestion. Protected RNA was analyzed by electrophoresis
with 6% acrylamide/8 mmol/L urea gels. The gels were
exposed overnight to x-ray film at -70°C in the presence of
intensifying screens. The size of the predicted
nucleotide-protected fragments was confirmed with a
[32P]-labeled RNA molecular weight ladder.
Relative mRNA levels were quantified by scanning densitometry (LKB
2222-020 Ultrascan XL laser densitometer) and normalized with respect
to GAPDH.
Protein Analysis
VSMCs were lysed in electrophoresis buffer (125 mmol/L
Tris-HCl [pH 6.8], 12.5% glycerol, 2% SDS, and 2.5% DTT) and
boiled for 10 minutes. The lysate was centrifuged at
14 000g for 20 minutes at 4°C, the supernatant collected,
and protein concentration determined by the bicinchoninic acid method
with serum albumin as the standard.39
Proteins (20 µg) were separated on 10% polyacrylamide gels
by SDS-PAGE and transferred to nitrocellulose membranes at 100 V for 1
hour. Membranes were blocked for 1 hour in PBS containing 0.1% Tween
20 and 3% nonfat milk and then incubated with the HO-1 antibody (1:500
dilution) in Tween 20 (0.1%) containing PBS for 1 hour. The membrane
was then washed in PBS and incubated for 1 hour with anti-rabbit
(1:7500 dilution) horseradish peroxidase–conjugated antibody. After
further washing with PBS, blots were incubated in commercial
chemiluminescence reagents (Amersham) and exposed to photographic film.
Relative protein levels were determined by scanning densitometry.
Measurement of Reactive Oxygen Species
The intracellular production of reactive oxygen species
was determined by measurement of the oxidation of
CM-H2DCFDA to the fluorescent compound
CM-H2DCF with a Cytofluor II multiplate
fluorimeter (Millipore) as previously described.40 SMCs
were preincubated in Hanks’ buffer containing
CM-H2DCFDA (5 µmol/L) for 20 minutes and
then stimulated with PDGF. Fluorescence was monitored at
excitation and emission wavelengths of 485 and 530 nm,
respectively.
CO Detection System
CO release by VSMCs was determined by use of a previously
described coincubation bioassay system8 28 41 in
which cGMP production in "detector" platelets layered
in suspension over monolayers of SMCs reflects the activation of
platelet soluble guanylate cyclase by SMC-derived CO.
Before addition of platelets to SMCs, the medium was aspirated and
the cells were thoroughly washed with PBS to ensure that platelets
were not exposed to any of the treatment compounds. In some
experiments, hemoglobin (50 µmol/L) was added to the
platelet suspension. After 45 minutes of incubation with the SMCs,
the platelet suspensions were collected in TCA (6% wt/vol),
briefly sonicated, and pelleted in a microfuge. Platelet lysates
were then extracted with 4 vol of water-saturated ether and assayed for
cGMP with a commercially available radioimmunoassay kit (New England
Nuclear-Dupont).
Platelet Preparation
Blood from drug-free donors was collected by antecubital vein
phlebotomy into 15% (vol/vol) acid-citrate-dextrose and
centrifuged at 220g for 14 minutes at 22°C. The
platelet-rich plasma was collected and then adjusted to pH 6.5 with
additional acid-citrate-dextrose, and creatine phosphate (5
mmol/L) and creatine phosphokinase (25 U/mL) were added. The
platelet-rich plasma was layered over a BSA density gradient and
centrifuged at 1620g for 16 minutes at 22°C.
Interface platelets were collected and subjected to repeated BSA
density gradient separation. Platelets were then gel-filtered
through Sepharose 2B-300 and collected in Tyrode’s buffer (in
mmol/L: NaCl 130, sodium citrate 10, Tris base 10,
NaHCO3 9, glucose 6, KCl 3,
CaCl2 1, MgCl2 0.9,
KH2PO4 0.8 [pH 7.35])
containing IBMX (0.1 mmol/L) when used in the CO detection
experiments or in MEM when used to generate platelet
releasates.
Platelet releasates were generated by incubating suspensions of platelets with collagen (20 µg/mL) for 15 minutes. The platelets were then removed by centrifugation at 1620g for 16 minutes, and the releasate was collected. In some experiments, active PDGF present in the releasate was neutralized by incubating the platelet releasate with the IgG fraction (50 µg/mL) of a PDGF-neutralizing polyclonal antibody for 60 minutes at 22°C.
Statistics
Results are expressed as mean±SEM. Statistical analysis
was performed with a Student’s two-tailed t test. Values of
P<0.05 were considered statistically significant.
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Results |
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Treatment of VSMCs with PDGF (30 ng/mL) resulted in the rapid induction of HO-1 mRNA and protein. PDGF markedly elevated HO-1 mRNA levels by nearly 9-fold within 1 hour of treatment, and HO-1 message gradually declined to basal levels after 8 hours of PDGF exposure (Figure 1
). In contrast, the induction of
HO-1 protein by PDGF was delayed, with a slight increase (1.4-fold)
observed at 2 hours, followed by a maximum 4-fold elevation at 4 and 8
hours. HO-1 protein levels (1.7-fold) remained elevated 24 hours after
PDGF stimulation (Figure 2).
PDGF-mediated increases in HO-1 mRNA and protein were
concentration-dependent (Figure 3) and
were specific for the HO-1 isoform because PDGF failed to stimulate
HO-2 expression (data not shown). Incubating SMCs with the protein
synthesis inhibitor cycloheximide (5 µg/mL) or with the
transcriptional inhibitor actinomycin D (2 µg/mL) blocked
the basal expression of HO-1 mRNA and protein and prevented the
PDGF-mediated induction of HO-1 mRNA and protein (Figure 4).
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Treatment of VSMCs with PDGF (30 ng/mL) resulted in an immediate rise
in the generation of reactive oxygen species that progressively
increased over 30 minutes (Figure 5A).
This PDGF-mediated increase in intracellular reactive oxygen species
was markedly attenuated by the antioxidant NAC (3 mmol/L) (Figure 5A). In addition, NAC (3 mmol/L) inhibited the induction of
HO-1 protein by PDGF (Figure 5B). In the absence of PDGF, NAC
minimally affected reactive oxygen production (data not shown)
or HO-1 protein expression (Figure 5B). Finally, incubation of
SMCs with actinomycin D (2 µg/mL) resulted in a decay of HO-1 mRNA
with a half-life of 
90 minutes (Figure 6). PDGF failed to alter the stability of
HO-1 message (Figure 6).
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) of NAC (3 mmol/L), and the fluorescence
of CM-H2DCF was monitored. For experiments measuring HO-1
protein expression, cells were treated with PDGF (30 ng/mL) for 6 hours
in the absence or presence of NAC (3 mmol/L), and HO-1 protein
levels were determined by Western blotting. Similar findings were
observed in 3 separate experiments.
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In subsequent experiments, HO activity was measured by monitoring SMC
CO synthesis. Because CO is a readily diffusable, membrane-permeable
gas that activates soluble guanylate
cyclase,19 26 27 28 HO activity was determined by
measurement of the intracellular concentration of cGMP in coincubated
detector platelets. Incubating platelets with SMCs that had
been treated with PDGF (30 ng/mL) for 6 hours resulted in a >3-fold
greater increase in platelet cGMP concentration than that found in
platelets exposed to untreated control SMCs (Figure 7). The stimulatory effect of
platelet cGMP levels by PDGF-treated SMCs was inhibited by
incubation of the SMCs with the HO inhibitor SnPP (20
µmol/L)41 or by addition of the CO scavenger hemoglobin
(50 µmol/L) to platelets during their incubation with
PDGF-treated SMCs (Figure 7). In contrast, treatment of SMCs
with methyl-L-arginine (L-NMA, 1 mmol/L) did not alter
the stimulatory effect of PDGF-treated SMCs on platelet cGMP levels
(Figure 7). In the absence of PDGF treatment, exposure of SMCs
to SnPP (20 µmol/L) or hemoglobin (50 µmol/L) did not
significantly affect the intracellular cGMP concentration of incubated
platelets (data not shown).
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PDGF is stored in platelet 
-granules and is released on
platelet activation by various stimuli, such as collagen. Treatment
of SMCs with the releasate from collagen-activated
platelets for 6 hours also stimulated HO-1 protein expression in a
platelet concentration–dependent manner, with maximum induction
observed at 2x108 platelets/mL (Figure 8A). The addition of a PDGF-neutralizing
antibody to the platelet releasate blocked the induction of HO-1 by
the releasate (Figure 8B). In contrast, nonimmune IgG failed to
modulate the stimulatory effect of the releasate (Figure 8B).
The addition of the PDGF-neutralizing antibody or of the nonimmune IgG
to untreated SMCs had no effect on HO-1 protein expression (Figure 8B).
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Discussion |
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The present study demonstrates that PDGF induces the expression of the HO-1 gene and the synthesis of CO by VSMCs. PDGF stimulates HO-1 mRNA and protein production in a concentration- and time-dependent manner, with the elevation in HO-1 message preceding the increase in HO-1 protein. In addition, treatment of SMCs with PDGF stimulates the production and release of CO, as demonstrated by the CO-dependent increase in intracellular cGMP levels in coincubated platelets.
The PDGF-induced upregulation of HO-1 gene expression is dependent on de novo RNA synthesis and probably involves transcriptional activation of the gene, because PDGF does not alter the stability of HO-1 mRNA. Although the molecular mechanism by which PDGF stimulates HO-1 expression is not known, PDGF induces the expression of several genes by stimulating the formation of the activator protein-1 (AP-1) family of transcription factors.42 43 In this respect, promoter studies have identified functional AP-1–responsive elements in the 5'-flanking region of the HO-1 gene.44 45 The capacity of cycloheximide to inhibit PDGF-induced HO-1 mRNA expression suggests that de novo AP-1 synthesis may be required for HO-1 gene expression.
The induction of HO-1 by PDGF is dependent on the production of reactive oxygen species. Consistent with earlier studies, we found that PDGF stimulates a marked increase in the intracellular synthesis of reactive oxygen intermediates.46 47 Moreover, we observed that the antioxidant NAC inhibits both the PDGF-mediated production of reactive oxygen species and the induction of HO-1 in VSMCs. These findings indicate that reactive oxygen intermediates, which are well-established inducers of HO-1,5 6 48 mediate the induction of HO-1 by PDGF. Interestingly, AP-1 is a redox-sensitive transcription factor,49 raising the possibility that reactive oxygen species stimulate HO-1 expression via AP-1 activation.
The ability of PDGF to rapidly induce the expression of the antioxidant protein HO-1 may provide an important cellular defense mechanism against oxidative injury. The induction of HO-1 in vascular cells leads to an increased resistance to oxidative stress, whereas HO-1 deficiency results in enhanced vascular cell injury.7 12 50 The protective effect of HO-1 arises, in part, from the HO-mediated formation of biliverdin and its subsequent conversion to bilirubin by biliverdin reductase.7 Bilirubin is an efficient scavenger of reactive oxygen species and inhibits lipid peroxidation.13 51 Interestingly, recent studies have correlated elevations in serum bilirubin concentration with a marked reduction in the risk of coronary artery disease.52 53 Thus, the ability of PDGF to induce HO-1 and the formation of bilirubin by VSMCs may provide blood vessels with cytoprotection against oxidative tissue injury.
The PDGF-induced increase in HO-1 gene expression is associated with an increase in HO activity as measured by CO synthesis. Incubation of platelets with PDGF-treated SMCs results in a significantly greater increase in platelet cGMP concentration than that in platelets exposed to untreated control SMCs. The SMC-mediated rise in platelet cGMP results from increased HO activity, because the HO inhibitor SnPP abrogates the cGMP-elevating effect of PDGF-treated cells. Furthermore, the CO scavenger hemoglobin reverses the increase in platelet cGMP evoked by the PDGF-treated cells. In contrast, the NO synthase inhibitor L-NMA fails to modulate platelet cGMP levels during their incubation with SMCs. These results demonstrate that SMC-derived CO, not NO, is responsible for the elevation in platelet cGMP levels. The capacity of PDGF to induce CO release from SMCs may provide an important adaptive mechanism to maintain vascular homeostasis at sites of vascular injury. We have recently shown that SMC-derived CO inhibits platelet aggregation,25 indicating a potential role for this gas in the development of thromboresistance after blood vessel injury.54 55 In addition, the release of CO by SMCs may also serve to preserve blood flow at sites of vascular damage by reducing blood vessel spasm and SMC proliferation.24
The physiological significance of our finding is further suggested by the observation that the releasate from collagen-activated platelets stimulates HO-1 expression. SMCs may be exposed to products released by adherent, activated platelets at a site of vascular injury. This HO-1 stimulatory effect of the platelet releasate is mediated by PDGF, because a neutralizing antibody directed against PDGF reverses its induction of HO-1 protein. The ability of platelets to induce HO-1 expression provides a mechanism whereby antioxidant heme metabolites and CO are specifically induced at sites of vascular trauma. In this model, circulating platelets are recruited to sites of vascular injury, where they are activated by interaction with subendothelial collagen, resulting in the release of PDGF and the local expression of HO-1. This limited focal induction of HO-1 to sites of vascular damage may be of physiological significance, because a recent study demonstrated that the global induction of HO-1 in the vasculature and the subsequent release of large amounts of CO contribute to the severe hypotension associated with endotoxin shock.29
The ability of PDGF to stimulate HO-1 gene expression and CO synthesis contrasts with our earlier findings showing that PDGF blocks inducible NO synthase gene expression and NO formation in VSMCs.34 35 36 These results indicate that PDGF exerts a divergent regulatory effect on the production of biologically active gases by vascular cells. They further suggest that at sites of vascular injury, where endothelial cells are lost or damaged and PDGF is present, the predominant gaseous messenger released by the blood vessel is CO. Interestingly, Motterlini et al56 recently demonstrated that HO-1–derived CO is the principal in vivo gaseous modulator of blood pressure after vascular surgery. Similarly, Pannen et al57 showed that CO rather than NO serves as the primary regulator of hepatic perfusion after hemorrhagic shock. These findings indicate that during conditions of vascular stress, blood vessels switch gaseous monoxide production from the synthesis of highly reactive and potentially toxic NO to the nonreactive stable gas CO. This shift in diatomic gas formation during stress conditions may prevent the potentially harmful actions of NO while still retaining the beneficial effects associated with soluble guanylate cyclase activation.
In conclusion, the present study demonstrates that PDGF induces HO-1 gene expression and the generation of CO in VSMCs. The induction of HO-1 may play an important cytoprotective role by catabolizing heme and by generating antioxidant molecules. In addition, the HO-1–catalyzed production of guanylate cyclase–stimulatory CO may serve to promote blood flow and fluidity at sites of vascular injury.
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute grants HL-59976 and HL-36045, the Veterans Affairs Merit Review Board, and a Grant-in-Aid from the American Heart Association. The authors thank Dr Genevieve Sparagna for assistance with the measurement of reactive oxygen species and Lan Liao for providing the vascular smooth muscle cells.
Received December 7, 1998; accepted April 26, 1999.
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