Increased expression of transforming growth factor-beta1 as a stabilizing factor in human atherosclerotic plaques.
OBJECTIVE
Transforming growth factor-beta (TGF-beta) is a growth factor/cytokine involved in vascular remodeling and atherogenesis. Recent studies in apolipoprotein E-deficient mice have demonstrated a pivotal role of TGF-beta in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques. Furthermore, inhibition of TGF-beta signaling has been shown to accelerate plaque formation and its progression toward an unstable phenotype in mice. However, if this mechanism is operative also in humans is still unknown. The aim of this study was to characterize the expression of TGF-beta1 in human carotid plaque and to correlate it with the extent of inflammatory infiltration and collagen content with the clinical signs of plaque instability.


METHODS
Plaques were obtained from patients undergoing carotid endoarterectomy and divided into symptomatic and asymptomatic according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for TGF-beta1 expression by Immunocytochemistry, Western, and Northern blotting analysis. Immunocytochemistry was used to identify CD68+ macrophages, CD3 T lymphocytes, HLA-DR+ cells, and alpha-smooth muscle cells. Procollagen and interstitial collagen content were analyzed by immunohistochemistry and Sirius Red staining, respectively.


RESULTS
Plaque TGF-beta1 mRNA was increased up to 3-fold in asymptomatic as compared with symptomatic plaques. Plaques from asymptomatic group had fewer (P<0.0001) macrophages and T lymphocytes compared with symptomatic plaques. TGF-beta1 gene was transcriptionally active as demonstrated by increased (P<0.0001) TGF-beta1 protein expression in asymptomatic plaques. Immunohistochemistry showed that TGF-beta was mainly expressed in plaque shoulder and was associated with a comparable increase (P<0.0001) in plaque procollagen and collagen content.


CONCLUSIONS
In conclusion, this study demonstrates the higher expression of TGF-beta1 in human asymptomatic lesions and provides evidence that TGF-beta1 may play an important role in the process of plaque stabilization.
Department of Medicine and Aging, School of Medicine, and Aging Research Center, Ce.S.I. Gabriele d'Annunzio University Foundation, Chieti-Pescara, Italy. fcipollone@unich.it
Francesco
F
Cipollone
Maria
M
Fazia
Gabriella
G
Mincione
Annalisa
A
Iezzi
Barbara
B
Pini
Chiara
C
Cuccurullo
Sante
S
Ucchino
Francesco
F
Spigonardo
Marcello
M
Di Nisio
Franco
F
Cuccurullo
Andrea
A
Mezzetti
Ettore
E
Porreca
D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D016893:Carotid Stenosis / Q000378:metabolism* / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C508960:TGFB1 protein, human