Articles |
From the Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, S-413 45 Göteborg, Sweden.
Correspondence to Gunnar Fager, MD, PhD, Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, S-413 45 Göteborg, Sweden.
Key Words: thrombin transcription factor platelet-derived growth factor fibroblast growth factor smooth muscle cells
| Introduction |
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Thrombin-induced receptor activation and intracellular signaling are prevented by substances that block the catalytic and/or receptor binding domains of thrombin. These substances also block thrombin-induced expression of PDGF and bFGF. Furthermore, thrombin-induced proliferation of vascular SMCs is blocked by antibodies to PDGF and FGF. Thus, the possibility must be considered that thrombin influences proliferation of susceptible SMCs by inducing an autocrine or paracrine stimulation via PDGF and/or bFGF.
| Enzymatic Properties of Thrombin |
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Enzymatically active thrombin (
-thrombin) is formed from the
circulating precursor prothrombin by hydrolytic cleavage (reviewed in
Reference 11 ). This hydrolysis is initially slow and catalyzed only by
factor Xa. Subsequently,
-thrombin activates factor V,
which operates as a cofactor to factor Xa and accelerates the formation
of
-thrombin. Furthermore, factor VIII is activated by
-thrombin to participate in the production of more
factor Xa.
-Thrombin belongs to the superfamily of serine proteases and cleaves
its target proteins C-terminally to R (one-letter code for
arginine) residues. Structural studies (reviewed in Reference 22 ) have
revealed a sequence in
-thrombin in which the catalytic site
containing an S-H-D motif lies immediately distal to arginine's
guanidine side-chain binding site (the arginine side-chain
pocket) (Fig 1
). Flanking these domains are regions involved in
specific hydrophobic and ionic interactions: proximal to the arginine
side-chain pocket is an apolar binding site, and distal to the
catalytic site is an anion-binding site (exosite).
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By its apolar and anion-binding sites,
-thrombin
specifically binds fibrinogen via hydrophobic and ionic
interactions.2 The Aa and Bb chains of the three-chain
fibrinogen molecule bind with slightly different amino acid motifs and
are hydrolyzed at the R16 and R14 residues,
respectively, at different rates. The enzymatic removal of the N
termini (fibrinopeptides A and B, respectively) creates
active fibrin monomers that polymerize into the fibrin mesh of the
developing blood clot.
-Thrombin is eliminated by proteolytic degradation and by binding to
inactivator molecules. A number of proteases are
involved in the formation of the inactive metabolites ß- and
-thrombin. AT III is the most important native
inactivator of
-thrombin in plasma.
-Thrombin
binds slowly to AT III to form the TAT complex, which is neither a
procoagulant nor a cell stimulator. Heparin binds AT III specifically
and significantly facilitates the subsequent binding to
-thrombin. This explains part of the anticoagulant activities of
heparin.
Cellular Effects of -Thrombin
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| Human Thrombin Cell Surface Receptor |
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Platelets, macrophages, arterial endothelial cells, and SMCs express thrombin receptor transcripts. The human receptor was originally cloned from megakaryocyte-like cells and then found in human platelets19 and endothelial cells.13 Human bloodderived monocytes (activated as well as inactive) exhibit trace levels of mRNA for the human receptor, whereas human alveolar and atherosclerotic intimal macrophages show an abundance of transcripts.20 In grossly normal areas of human arterial specimens, only endothelial cells show significant signals from receptor protein and mRNA by immunohistochemistry and in situ hybridization. In atherosclerotic areas, however, endothelial cells as well as intimal (not medial) SMCs and macrophages show positive signals for receptor protein and mRNA.20 These results are not unequivocal and need corroboration. However, they raise the possibility that the expression of thrombin receptors is transcriptionally upregulated among growth-stimulated intimal SMCs and activated macrophages.
Indeed, Zhong et al,21 who recently cloned the rat thrombin receptor, found that it was expressed in growth (bFGF)stimulated but not in growth-arrested rat vascular SMCs in vitro. bFGF and thrombin have synergistic effects in vascular SMCs,22 but antibodies to bFGF rendered these cells insusceptible to thrombin (but not to PDGF) stimulation.23 Consequently, it cannot be currently excluded that SMCs are rendered susceptible to the growth-promoting effects of thrombin by mitogens like FGF via induction of thrombin receptors.
| Activation of the Thrombin Receptor |
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Proteolytic cleavage at arginine residue 41 yields a new N terminus to the receptor (NH3-S42-F43-L44-L45-). A synthetic oligopeptide containing this sequence, but not the variant oligopeptide (NH3-F-S-L-L-), is able to induce maximum mobilization of intracellular Ca2+ in oocytes expressing the wild-type thrombin receptor.13 Although resistant to thrombin activation, oocytes expressing the mutant receptors R41A or S42P are fully sensitive to stimulation with the SFLL-containing oligopeptide. This shows that proteolytic cleavage of the receptor by thrombin generates a new N-terminal sequence that is able to activate the receptor intrinsically. For the activation of trypsinogen, a similar mechanism, by which a proteolytic cleavage unmasks an internal ligand that folds and binds within the trypsin molecule, has been shown. This induces a conformational change resulting in active trypsin.26 27 Conceivably, the liberated intrinsic ligand sequence folds and binds to a binding site within the external domain of the thrombin receptor, inducing the receptor-mediated cellular response. Brass et al28 showed that active thrombin is also necessary for the appropriate folding of the tethered ligand and the subsequent internalization of the thrombin receptor.
A synthetic heptapeptide (NH3-S-F-F-L-R-N-P-COOH), which is
the hamster homologue to the human SFLL-sequence,29 is as
efficient as but less potent than
-thrombin in stimulating a
number of subcellular events in CCL39 hamster
fibroblasts.19 Anything shorter than the pentapeptide
(NH3-S-F-F-L-R-COOH) is, however, completely inefficient.
These results indicate a novel mechanism for receptor activation
consisting of a specific proteolytic unraveling of a tethered
endogenous ligand sequence.
The importance of the anion exosite binding domain of the receptor is
suggested indirectly by experiments with Xenopus oocytes
expressing the wild-type thrombin receptor.13 Hirudin
and hirugen, known to bind to the anion exosite of thrombin without
completely blocking hydrolysis of small-substrate molecules (ie,
without blocking the catalytic site),17 inhibit activation
of the receptor. Proteolytically inactive thrombin (mutant S205A)
carrying an intact receptor-binding motif fails to stimulate
oocytes expressing the receptor. The same is true for
-thrombin,
which is inactivated by binding to the catalytic
site-blocker PPACK, which leaves the acid motif free. Likewise, the
natural thrombin inhibitor AT III also blocks
thrombin-induced receptor stimulation and human
arterial SMC proliferation.30
| Intracellular Signaling Pathways |
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-thrombin induces rapid acidification and
subsequent gradual alkalinization that is dependent on the
Na+-H+ exchanger (Reference 3131 and reviewed in
Reference 3232 ). Within seconds,
-thrombin also activates
PLC and induces the hydrolysis of phosphoinositides
into inositol-3 and inositol-2 phosphates and, subsequently, the
production of prostaglandin
I2.6 33 This is a likely explanation for the
equally rapid increase in intracellular free Ca2+ as well
as the subsequent activation of the Na+-H+
exchanger. Phosphorylation of the cytosolic domain of
the thrombin receptor by G proteincoupled kinases seems to be an
initiating event.34 The number of
phosphorylated thrombin receptors depends on the
concentration of
-thrombin and the subsequent PLC activity in
turn on the cumulative number of stimulated
receptors.35
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-Thrombin, bFGF,36 37 and PDGF38 39
activate MAPks. Thrombin induces two bursts of MAPk activity.
Only the later burst is blocked by pertussis toxin, suggesting a G
proteincoupled receptor mechanism.37 39 bFGF and
PDGF induce only the late burst of MAPk via their tyrosine
kinasecoupled receptors. This burst of activity is necessary for
cell proliferation.39 40
-Thrombin dose-dependently inhibits forskolin-stimulated
adenylate cyclase activity, with a subsequent decrease in
intracellular cAMP levels in human SMCs41 as well as in
hamster fibroblasts.19 The effect of
-thrombin is
counteracted by pertussis toxin, suggesting that suppression of
adenylate cyclase activity is mediated by G proteins.
In hamster fibroblasts, oligopeptides corresponding to five or more
amino acids of the N terminus of the tethered ligand sequence
(NH3-S-F-F-L-R-) are, alone, as efficient as
-thrombin in influencing PLC and adenylate cyclase
activities.19 However, only in the presence of added
conventional growth factors does the activation of the receptor result
in DNA synthesis.19 Furthermore, the same tethered
ligandderived oligopeptides activate human platelets
in vitro to release of 14C-serotonin.
| Differential Regulation of Proto-oncogene and Growth Factor Expression |
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-Thrombin induces a concentration-dependent transient
increase in c-fos mRNA in bovine,42
rat,31 and human41 SMCs. An increase is
evident within 30 minutes, peaks after 60 minutes, and vanishes within
6 hours (Fig 2
-thrombin stimulates
intracellular protein synthesis but not DNA synthesis or cell
proliferation in rat SMCs. However, this is at variance with the
conclusions of others, who have found DNA synthesis19 43
as well as cell proliferation12 41 42 44 after stimulation
with
-thrombin. In human SMCs in culture,
-thrombin
induces transient expressions of c-fos and
c-myc.41 The former peaks after 15 minutes.
This delay is comparable to that after stimulation with PDGF. However,
c-myc peaks only at 8 hours after stimulation with
-thrombin. In contrast, stimulation with PDGF induces a
transient expression of both proto-oncogenes within minutes
(reviewed in Reference 4545 ).
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In the presence of exogenous PDGF, human SMCs proliferate and exhibit a proliferative morphology without contractile protein filaments in vitro.46 47 48 49 50 51 In the absence of PDGF, they become growth-arrested and express contractile filaments. PDGF has been implicated as a critical mitogen in occlusive arterial diseases (reviewed in References 52 and 5352 53 ). However, there are a number of other cytokines known to influence the properties of SMCs that might be important in this context. In the rat carotid balloon injury model, bFGF has recently been suggested to be an inducer of proliferation among mature medial SMCs, and PDGF has been cited as a chemoattractant and secondary mitogen among these initiated SMCs.54 Consequently, bFGF may induce the expression of thrombin receptors,21 22 23 with thrombin subsequently inducing the expression of endogenous PDGF. Indeed, human SMCs respond to thrombin stimulation in vitro by a transcriptionally regulated secretion of PDGFA chain homodimers and epidermal growth factor.55
Using Northern blot hybridization, Okazaki et al43 showed
that
-thrombin induces an upregulation of PDGFA chain but not
B chain mRNA in rat SMCs in vitro. Simultaneously, they
noticed a suppression of PDGF
- and ß-receptor mRNA. These
effects were maximal after 6 hours and inhibited by PPACK. The
suppression of PDGF receptor mRNA may be a primary result of
stimulation with
-thrombin. It could be speculated, however,
that it is related to the downregulation of PDGF receptors after
stimulation by PDGF in vitro (reviewed in References 45, 52, and 5345 52 53 ).
Therefore, these findings may only indicate that the
-receptors
were indeed stimulated by endogenous PDGFA chain
homodimers.
The latter interpretation is consistent with observations in vivo. Up to 6 hours after balloon injury to the brachial artery of baboons, there is an increase in PDGFA chain transcripts in total RNA prepared from the injured arterial tissue.43 However, this increase is significantly reduced if PPACK is administered in conjunction with the trauma. Arterial injury did not suppress PDGF ß-receptor mRNA in these experiments.
These data suggest the possibility that
-thrombin induces
expression of PDGF that stimulates cell proliferation by induction of
both proto-oncogenes c-fos and c-myc
(reviewed in References 45, 52, and 5345 52 53 ). Consistent with this
is the observation that DNA synthesis peaks 20 to 28 hours after
stimulation with PDGF but 10 to 20 hours later in human41
as well as rat12 SMCs after stimulation with
-thrombin. Consequently,
-thrombin may induce cell
proliferation via the induction of PDGF and, subsequently,
c-myc expression. Wilson et al56 found that rat
vascular SMCs in vitro that were subjected to cyclic mechanical strain
in the presence of
-thrombin synthesized more DNA and exhibited
a transcriptional upregulation of PDGF production. This DNA
synthesis was inhibited by antibodies to PDGF.
Apart from similarities discussed above, there seem to be important
differences between thrombin and PDGF stimulation regarding
intracellular signaling events (Table
). Stimulation of thrombin
receptors has no effect on protein kinase C but decreases
adenylate cyclase and as a consequence the
production of cAMP and prostaglandin
I2.19 In contrast, stimulation of PDGF
receptors increases adenylate cyclase and probably protein
kinase C.45 57 Activation of appropriate kinases within
the PDGF receptor by tyrosine phosphorylation is a
prerequisite for mitogenic stimulation with
PDGF.58 59 As discussed earlier, PDGF rapidly induces
proto-oncogenes c-fos and c-myc, followed by
DNA synthesis. In contrast, thrombin rapidly induces only
c-fos. Induction of c-myc and DNA synthesis
follow much later after thrombin stimulation and only after the
endogenous PDGFA chain production has been
upregulated. It cannot be excluded that the controversy regarding
whether SMCs are susceptible to thrombin stimulation in the absence of
exogenous growth factors (see above) may relate to the varying
contributions of endogenous growth factors.
Less seems to be known about the intracellular events following FGF
stimulation than after PDGF or
-thrombin stimulation (Table
).
However, the FGFs seem to operate via partly different signaling
pathways. The FGFs increase protein kinase activities60 61
but not cAMP production61 62 and increase
cytosolic Ca2+-dependent c-fos63 64 65
and c-myc64 expression and the proliferation of
glomerular mesangial SMCs66 and
bovine endothelial67 cells. bFGF
activates phospholipase D but does not induce the breakdown of
phosphoinositides.68
-Thrombin also upregulates mRNA for the bFGF in rat vascular
endothelial cells69 and dermal
fibroblasts.70 Weiss and colleagues22 23 have
shown a synergistic mitogenic effect of
-thrombin
and bFGF in rat vascular SMCs in vitro. They have also shown a rapid
increase in cytosolic bFGF and that the mitogenic response
to
-thrombin was inhibited by antibodies to bFGF. Consequently,
it cannot be excluded that
-thrombin induces an expression of
endogenous FGF and PDGF that may be the direct stimuli to
cell proliferation.
| Thrombin Inhibitors and Cell Proliferation |
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-thrombin.30 | Concluding Remarks |
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First, locally adhering and agglutinating platelets lyse and release preformed PDGF from their alpha granules. This process is likely suppressed if thrombin is prevented from stimulating its platelet receptor.
Second, endothelial cells expressing thrombin receptors
constitutively respond to
-thrombin stimulation by bFGF
production. This may in turn stimulate thrombin receptor
expression in SMCs.
Third, such SMCs would be likely to respond to
-thrombin by PDGF
production and proliferation. SMCs in the intima of
atherosclerotic lesions express transcripts for the PDGFA
chain.73 Although rat vascular SMCs in vitro express
bFGF,22 23 it is presently unclear whether this occurs
in human atherosclerotic lesions. Stimulation of thrombin receptors
present on growth factorstimulated intimal SMCs leads to the
endogenous production of PDGF and, possibly, bFGF.
Medial differentiated SMCs are insusceptible to thrombin stimulation,
suggesting that they must first be rendered susceptible by factors
other than thrombin. Only the thrombin-dependent part of the
endogenous PDGF and bFGF production is likely
blocked by the thrombin inhibitors.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received May 23, 1994; accepted May 11, 1995.
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