Role of platelet-derived growth factor and transforming growth factor beta1 the in the regulation of metalloproteinase expressions.
BACKGROUND
We investigated the role and influence of platelet derived growth factor (PDGF) and transforming growth factor beta1 (TGF) in the pathologic mechanism at the basis of plaque instability regulating the expression of matrix metalloproteinases (MMPs).


METHODS
Plaques obtained from 70 patients who underwent carotid endarterectomy were classified histologically as stable or unstable. Serum levels of PDGF and TGF were measured pre- and postoperatively. The serum activities of MMP-2 and MMP-9 were also analyzed. Human umbilical artery smooth muscle cells (HUASMCs) were stimulated in vitro with PDGF at various concentrations (20 and 50 ng/mL) and TGF (2 and 5 ng/mL) in a serum-free medium. The release of MMPs in the conditioned medium was assessed by enzyme-linked immunosorbent assay. Release of the MMPs was confirmed by Western blot analysis; their activity and expression were determined by zymography and reverse transcription-polymerase chain reaction. Specific inhibition tests were performed on HUASMCs to evaluate the role of these growth factors.


RESULTS
Forty-two (60%) patients had an unstable carotid plaque and 28 (40%) a stable plaque. Preoperatively, patients affected with unstable carotid plaques had higher PDGF and lower TGF plasma levels than patients with stable carotid plaques (P < .001); the levels returned to normal at 1 and 30 days postoperatively, compared with 20 non-operated healthy volunteers. Release, activity, protein level, and expression of MMPs in PDGF-stimulated HUASMCs were greater than in the controls (P < .001), whereas these values in the TGF-stimulated HUASMCs were lower (P < .001). The addition of monoclonal anti-PDGF antibodies decreased the release, activity, protein level, and expression of MMPs, whereas the addition of monoclonal anti-TGF antibodies increased the release, activity, protein level and expression of MMPs (P < .001).


CONCLUSIONS
TGF seems to be an important stabilizing factor and prevents plaque rupture through the decrease of MMPs.
Borrelli
Valeria
V
Department of Surgery "Pietro Valdoni", University of Rome "La Sapienza", Rome, Italy.
di Marzo
Luca
L
Sapienza
Paolo
P
Colasanti
Marco
M
Moroni
Enrico
E
Cavallaro
Antonino
A
D000368:Aged; D000369:Aged, 80 and over; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D016893:Carotid Stenosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D016894:Endarterectomy, Carotid; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000032:analysis / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9