(Hypertension. 1997;30:922-927.)
© 1997 American Heart Association, Inc.
Articles |
Parathyroid Hormone–Related Protein Upregulates Interleukin-1ß–Induced Nitric Oxide Synthesis
From the Department of Geriatric Medicine, Osaka University Medical School, Japan.
Correspondence to Shigeto Morimoto, MD, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan.
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Abstract |
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Abstract The effect of parathyroid hormone–related protein on interleukin-1ß–induced nitric oxide production was studied in rat vascular smooth muscle cells. Interleukin-1ß time- and dose-dependently enhanced the production of nitrite, a stable metabolite of nitric oxide. Parathyroid hormone–related protein(1-34) alone up to 10-7 mol/L had no obvious effect, but significantly increased the cytokine-induced nitrite production. RNA analysis revealed that the synergistic effect of parathyroid hormone–related protein(1-34) resulted from a potentiation of the expression of inducible nitric oxide synthase and GTP-cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is a cofactor of nitric oxide synthase. The increased nitric oxide release induced by interleukin-1ß or interleukin-1ß with parathyroid hormone–related protein(1-34) was completely inhibited by coincubation with 3x10-3 mol/L NG-monomethyl-l-arginine, a competitive inhibitor of nitric oxide synthase, or with 10-3 mol/L 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I. Endothelin-1 potentiated interleukin-1ß induction of nitric oxide, which might be mediated by endogenous parathyroid hormone–related protein. Neutralization of exogenous or endogenous parathyroid hormone–related protein with antibody attenuated the synergistic effect of parathyroid hormone–related protein, but did not affect interleukin-1ß induction of nitric oxide. These results suggest that locally produced parathyroid hormone–related protein acts as a synergistic regulator upregulating interleukin-1ß–induced nitric oxide synthesis in the cardiovascular system, and thereby may affect vascular tone and/or vascular remodeling after vascular injury in some pathological processes such as atherosclerosis and hypertension.
Key Words: parathyroid hormones • interleukin-1 • nitric oxide • RNA, messenger • muscle, smooth, vascular • rats
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Parathyroid hormone–related protein was originally characterized as a tumor product responsible for hypercalcemia of malignancy1 and was subsequently found to be produced in a variety of normal tissues, including VSMCs and endothelial cells.2 3 PTHrP has proven to be a potent vasorelaxant and is therefore considered to play a critical role in the local modulation of vascular smooth muscle functions.4 5 6 PTHrP increases cAMP accumulation and inhibits DNA synthesis in cultured VSMCs,7 and inhibits the production of endothelin-1, an endothelium-derived vasoconstrictor and growth factor for VSMCs, in cultured endothelial cells,8 suggesting a possible role of PTHrP as an autocrine and/or paracrine regulator in maintaining VSMCs in a contractile state. An overexpression of PTHrP gene has been observed in the intima of injured rat carotid arteries and human restenotic coronary lesions.9 10 It has been found that the expression of PTHrP in rat aortic smooth muscle cells can be stimulated by some vasoactive agents, such as angiotensin II, endothelin-1, and thrombin.2 Although these studies suggest that locally produced PTHrP may participate, together with other vasoactive agents, in the regulation of VSMC growth and other functions such as contractility under physiological or pathological conditions, what events might occur subsequently after the overexpression of PTHrP, and whether the locally produced PTHrP might interact with other locally produced factors in some pathological processes such as atherogenesis, remain to be explored.
NO is an unstable but multifunctional molecule that mediates many pathophysiological processes.11 12 iNOS has been found in particular in macrophages and VSMCs, which are both essential cells in the atheromatous plaque.13 iNOS can be induced by immunoinflammatory mediators (endotoxin and certain cytokines), and it produces a large amount of NO,12 which is considered to be toxic to many cell types and may induce apoptosis of vascular smooth muscle.14 15 16 17 Some cytokines including IL-1ß are found to be expressed not only by macrophages but also by endothelial cells and VSMCs present in the atherosclerotic plaque.18 IL-1ß is known to induce a large amount of NO production by increasing iNOS expression in vitro and in vivo.19 It was reported that esterified cholesterol enrichment of VSMCs in culture upregulates cytokine- and lipopolysaccharide-iNOS activities.20 Increased generation of NO has been found in VSMCs after balloon injury in vivo.21 It is suggested that the modification of NO synthesis might play a role in atherogenesis or vascular remodeling. However, the possible involvement of overexpressed PTHrP after vascular injury in the modification of NO synthesis has not been clarified.
The present study was performed to investigate whether PTHrP may have any effect on IL-1ß–induced NO production and iNOS messenger RNA expression in cultured VSMCs. Because the activity of iNOS requires tetrahydrobiopterin (BH4) as a cofactor, and the synthesis of the latter is regulated by the activity of GTPCHI,22 the effects of PTHrP and IL-1ß on this pathway were also studied.
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Methods |
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Materials
Human PTHrP(1-34) was purchased from Peptide Institute Inc. Recombinant human IL-1ß was obtained from Genzyme. L-NMMA, db-cAMP, forskolin, DAHP, and BSA were purchased from Sigma Chemical Co. dl-Isoproterenol hydrochloride was obtained from Wako Pure Chemical Industries. DMEM was from Nissui Pharmaceutical Co. All other materials used were commercial products of the highest grade available.
Cell Culture
VSMCs were isolated from rat thoracic aorta (male Wistar rat, 8
weeks old) as described previously23 and cultured in
100-mm culture dishes in DMEM supplemented with 10% fetal calf serum,
100 IU/mL penicillin G, and 100 µg/mL streptomycin at 37°C
in a humidified atmosphere of 95% air and 5% CO2. The
cells were used between passages 4 and 8.
Determination of Nitrite
VSMCs released with trypsin from stock cultures were seeded on
96-well culture plates at a density of 104 cells/well in
DMEM with 10% fetal calf serum. At confluence after a 3- or 4-day
incubation, the cells were washed twice with serum-free DMEM and then
incubated in serum-free DMEM containing 1 g/L BSA for 24 hours.
The medium was then refreshed and various agents were added as
indicated in "Results." The release of NO from cultures was
assessed by determination of nitrite, a stable metabolite of NO, using
Greiss reagent (a 1:1 mixture of 1% sulfanilamide and 0.1%
naphthylethylenediamine in 2% phosphoric acid).24
Determination of Protein
In some experiments, cell protein content was measured to
exclude affection of cell growth to estimation of nitrite
production. VSMCs were cultured on 96-well culture plates as
mentioned above. After exposure to various agents for 24 hours, the
cells were washed twice with ice-cold phosphate buffered saline, and
then 200 µL 0.1 mol/L NaOH was added to each well to dissolve
the cell proteins. Protein content was measured by the method of Lowry
et al,25 with BSA used as a standard.
Northern Blot Analysis
Cells cultured in 100-mm dishes at confluence were starved in
serum-free DMEM containing 1 g/L BSA for 24 hours, and then
incubated in fresh DMEM containing 1 g/L BSA and other agents
for 24 hours as indicated in "Results." Total RNA was then
extracted from VSMCs by standard procedures using ISOGEN (Nippon Gene).
Briefly, the cells were washed once with ice-cold phosphate buffered
saline and then detached with a "policeman" into 1 mL ISOGEN. The
solution was mixed with 0.2 mL chloroform. After
centrifugation at 12 000g at 4°C for 15
minutes, the supernatant was removed to a new tube and mixed with an
equal volume of isopropanol to precipitate RNA. After
centrifugation as above, the pellet was washed with
75% ethanol, recentrifuged at 10 000g at 4°C for
5 minutes, air-dried, and then dissolved in RNase-free water. The
concentration of RNA was estimated from the absorbance at 260 nm. The
RNA (15 µg) was electrophoresed on 1% agarose-formaldehyde
gels in 3-(N-morpholino)propanesulfonic acid buffer, pH 7.0,
transferred to Hybond nylon membranes with 20x SSC as blotting buffer,
and cross-linked to membrane by UV irradiation followed by baking at
80°C for 2 hours. Methylene blue staining was used to verify
ribosomal subunit integrity. After prehybridization, the membranes were
hybridized with randomly primed [
-32P]dCTP–labeled
probes at 55°C as previously described.26 The probe used
in the studies was a 1.8-kb cDNA fragment of murine iNOS. The membranes
were then washed under high stringency conditions (the final wash was
performed at 60°C in 0.2x SSC/0.1% sodium dodecyl sulfate
for 30 minutes). The membranes were subsequently stripped and
rehybridized with a human
glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) cDNA
probe (1.1-kb) (Clontech Laboratories, Inc). The size of the iNOS
transcript was estimated from the positions of 28s and 18s ribosomal
RNA.
RT-PCR
Analysis of messenger RNA levels for GTPCHI by RT-PCR
was performed by standard methods. Briefly, the first strand DNA was
synthesized from 0.5 µg total RNA using random 9-mer primers and
Avian Myeloblastosis Virus reverse transcriptase (Takara Shuzo Co),
followed by PCR amplification using synthetic gene-specific primers for
rat GTPCHI (forward 20-mer, 5'-CCG CTT ACT CGT CCA TCC TG-3'; reverse
20-mer, 5'-CCT TCA CAA TCA CCA TCT CG-3') with the following schedule:
denaturation, annealing and extension at 94°C, 60°C, and 72°C for
1 minute, 1 minute 30 seconds, and 1 minute 30 seconds, respectively,
for 25 cycles. RT-PCR for GTPCHI amplified a 183-bp sequence between
+191 and +373 of rat GTPCHI cDNA. The PCR product of GTPCHI was
confirmed by using a restriction endonuclease EcoO109I,
which digested the +225 site of GTPCHI cDNA. To ensure that equal
amounts of reverse-transcribed RNA were added to the polymerase chain
reaction, the parallel amplification of GAPDH messenger RNA was
performed as an internal reference, using forward 20-mer, 5'-GCC ATC
AAC GAC CCC TTC AT-3', and reverse 20-mer, 5'-CGC CTG CTT CAC CAC CTT
CT-3', which should give a 702-bp product. PCR products were
electrophoresed on a 2% agarose gel containing ethidium bromide and
visualized by UV-induced fluorescence. A HaeIII
digest of 
174 DNA (GIBCO-BRL Life Technologies, Inc) was
used as a size marker.
Statistical Analysis
Results are expressed as mean±SD. Statistical analysis
was performed by one-way ANOVA and Student's t test with
unpaired data. A value of P<.05 was considered to be
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effect of PTHrP on IL-1ß–Induced NO Production
As shown in Fig 1
, the
production of nitrite in cultured VSMCs was significantly
enhanced by IL-1ß in a dose- and time-dependent manner. The maximal
and half-maximal stimulation by IL-1ß were observed at concentrations
of 20 and 2.5 ng/mL, respectively. When the cells were exposed
to 10 ng/mL IL-1ß, a rapid increase of nitrite
production was observed within a 48-hour incubation.
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PTHrP(1-34) showed a synergistic effect with IL-1ß on nitrite
production. The effect of PTHrP(1-34) was
concentration-dependent. At a concentration of
10-7 mol/L, PTHrP(1-34) increased
IL-1ß–induced nitrite production about 90% (Fig 2A). PTHrP(1-34) alone had no obvious
effect. Nitrite production induced by both IL-1ß alone and by
IL-1ß with PTHrP(1-34) was completely inhibited by
3x10-3 mol/L L-NMMA, a competitive
inhibitor of iNOS (Fig 2B). Furthermore, coincubation of
the cells with 10-3 mol/L DAHP, an
inhibitor of GTPCHI, significantly attenuated both the
IL-1ß– and the IL-1ß plus PTHrP(1-34)–induced increase of nitrite
accumulation (Fig 2C).
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To examine whether the increases in nitrite production could be
influenced by changes in cell number, the cell protein content in
cultures treated for 24 hours with PTHrP(1-34), IL-1ß, and DAHP was
measured. Results in Fig 3 show a reduced
protein content in cultures treated with PTHrP(1-34) alone, but no
changes in cultures treated with IL-1ß or IL-1ß plus PTHrP(1-34),
suggesting that IL-1ß– or IL-1ß plus PTHrP(1-34)–induced nitrite
production was not due to VSMC proliferation. Although DAHP
reduced cell protein content dose-dependently, the extent of decreases
in cell protein content cannot explain its complete inhibition of
nitrite production.
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It is known that PTHrP stimulates VSMCs to produce cAMP, which has been
recognized as the major second messenger for PTHrP to trigger a series
of intracellular events.7 The effect of PTHrP on
IL-1ß–induced NO production was compared with those of
db-cAMP, isoproterenol, and forskolin. Similar to PTHrP(1-34), db-cAMP
at 10-4 mol/L, isoproterenol at
10-4 mol/L, and forskolin at
10-5 mol/L, alone showed no obvious
effects on nitrite production but significantly augmented the
stimulatory effect of IL-1ß by about 64%, 109%, and 36%,
respectively. Addition of 3x10-3 mol/L
L-NMMA completely inhibited the induced nitrite production
(Fig 4).
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To examine whether endogenously produced PTHrP from VSMCs
could contribute to the synergistic effect, the cells were treated with
or without endothelin-1 (10-7 mol/L)
for 3 hours in the presence or absence of a monoclonal antibody (3F5,
purified IgG) against PTHrP(1-34) (kindly donated by Dr Jane M. Moseley
of St Vincent's Institute of Medical Research) or control IgG and then
exposed to IL-1ß, PTHrP(1-34), or vehicle for 24 hours. The results
in Fig 5 show that the neutralizing
antibody had no effect on IL-1ß–induced nitrite release but that it
significantly inhibited the synergistic effect of exogenously added
PTHrP(1-34). There was a higher level of nitrite production in
endothelin-1–pretreated cultures than in unpretreated cultures after
exposure to IL-1ß. The nitrite production in
endothelin-1–pretreated cultures was partially attenuated by the
neutralizing antibody. Control IgG showed no effect on nitrite
production.
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Effect of PTHrP on IL-1ß–Induced iNOS Expression
Northern blot analysis showed an increased level of iNOS
messenger RNA in VSMCs exposed to 10 ng/mL IL-1ß for 24 hours.
PTHrP(1-34) alone at 10-7 mol/L did not
induce iNOS gene expression, but it markedly enhanced the iNOS
messenger RNA level induced by IL-1ß (Fig 6).
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Effect of PTHrP on GTPCHI Expression
Results in Fig 7A show a 183-bp
GTPCHI PCR product (lane 1) and a 148-bp digestive product by
EcoO109I (lane 2). The RT-PCR analysis for GTPCHI
expression revealed that PTHrP(1-34) also increased the expression of
GTPCHI stimulated by IL-1ß (Fig 7B). GTPCHI messenger RNA was
increased in IL-1ß–treated cells. PTHrP(1-34) potentiated the
stimulatory effect of IL-1ß on GTPCHI gene expression.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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PTHrP and IL-1ß both can be locally synthesized by VSMCs and macrophages present in the atherosclerotic plaque,2 9 18 but their interaction is unclear. IL-1ß has been recently found to be a potent stimulator of NO synthesis by inducing iNOS expression in VSMCs.19 21 27 In the present study, we demonstrated that PTHrP(1-34), a synthesized fragment of human PTHrP, significantly potentiated the stimulatory effect of IL-1ß on NO synthesis by increasing IL-1ß–induced expression of iNOS and GTPCHI. The synergistic effect of PTHrP(1-34) with IL-1ß was mimicked by db-cAMP, a permeable form of cAMP, isoproterenol, a ß2-adrenoceptor agonist that is known to exert its physiological effects by elevating intracellular cAMP as the second messenger, and forskolin, an activator of adenylate cyclase, suggesting that the effect of PTHrP(1-34) is mainly mediated through a cAMP signal pathway.
The synergistic effect of cAMP-elevating agents with IL-1ß on NO
production in this study is consistent with previous
findings by others.28 29 PTHrP is known to increase
intracellular cAMP level in VSMCs,7 and its synergistic
effect on NO production was similar to that of other
cAMP-elevating agents. Although our results indicate that PTHrP
potentiated IL-1ß–induced NO production through increasing
the expression of iNOS and GTPCHI, the mechanism by which PTHrP exerts
the synergistic effect remains unknown, because neither NO
production nor iNOS expression could be induced by PTHrP alone.
The reports that cAMP markedly prolongs the half-life of iNOS messenger
RNA may partly explain the synergistic effect on increasing iNOS
messenger RNA levels.28 30 It has also been reported that
cAMP stimulates the expression of GTPCHI followed by the synthesis of
tetrahydrobiopterin, which is a cofactor required for iNOS
activity.22 31 Other possibilities for the synergistic
mechanisms, including the modulation of the transcription factors such
as nuclear factor–
B, a protein that is known to be involved in iNOS
expression, and the regulation of IL-1 receptors, cannot be
excluded.
The role of PTHrP as a locally synthesized peptide in many normal tissues including VSMCs remains largely unknown. Although vasoactive or atherogenic agents, such as angiotensin II, endothelin, and thrombin, have been demonstrated to stimulate PTHrP messenger RNA expression and PTHrP production in VSMCs in vitro,2 and it has been recently reported that smooth muscle cells in atherosclerotic coronary arteries overexpressed PTHrP and the level of PTHrP expression was correlated with the degree of coronary artery stenosis,9 10 evidence seems not to suggest that PTHrP cooperates with these atherogenic agents, because of its potent roles in inhibiting endothelin-1 production in vascular endothelial cells,8 in inducing vasodilatation,4 5 6 and in inhibiting VSMC proliferation,7 which are apparently opposite to the effects of the above atherogenic factors. Neutralization experiments showed that PTHrP(1-34)–specific antibody did not affect nitrite production in cultures treated with IL-1ß alone, suggesting that PTHrP might express in a very low level in VSMCs under usual conditions. However, IL-1ß–induced nitrite production was increased by pretreatment of the cells with endothelin-1, and this increase was partially attenuated by PTHrP(1-34)–specific antibody, suggesting that an increased production of endogenous PTHrP by endothelin-1 stimulation could be, at least partly, responsible for the effect of endothelin-1 on IL-1ß–induced NO production. Thus, the synergistic effect of PTHrP on IL-1ß–stimulated iNOS expression and NO synthesis in cultured VSMCs suggests that PTHrP as a locally synthesized peptide may play an important role in modulating the immune response occurring at sites of injury in an autocrine and/or paracrine manner. NO, in addition to its potent vasodilator effect, has been identified as a potent inhibitor of platelet aggregation32 and a major factor responsible for the prevention of platelet and leukocyte adhesion to the vascular wall.33 34 NO has also been shown to inhibit mitogenesis and proliferation of VSMCs.35 The expression of iNOS, however, is mostly involved in infection or inflammation and is geared toward host defense.36 It has been reported that IL-1 induces secretion of platelet-derived growth factor by VSMCs, and this may account for the growth-promoting effect of IL-1.37 However, IL-1 also induces production of growth-inhibitory factors such as prostaglandin24 38 and NO. The in vivo significance of a local IL-1 release in the arterial wall is therefore unclear. Fukuo et al17 recently reported that a large amount of NO released from VSMCs may induce apoptosis in VSMCs themselves and induce upregulation of Fas via a cGMP-independent mechanism, and thus could trigger the remodeling of atherosclerotic vessels. We hypothesize that the role of PTHrP in potentiating IL-1ß–induced NO synthesis may represent a synergistic contribution of IL-1ß to vascular remodeling, and may protect against a later step in atherogenesis and fibrous plaque formation, and keep the vasculature in a relaxed state. Further studies are required to clarify its underlying significance.
In conclusion, PTHrP acts as a locally produced synergistic factor with IL-1ß in the induction of NO synthesis in the cardiovascular system, and thereby may affect vascular tone and/or vascular remodeling after vascular injury in pathological processes such as atherosclerosis and hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank Taeko Kaimoto for her technical assistance and Tomoko Adachi for her secretarial assistance.
Received September 8, 1996; first decision October 16, 1996; accepted March 3, 1997.
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References |
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