Published Online
on August 5, 2004

A more recent version of this article appeared on October 1, 2004

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Submitted on April 8, 2004
Revised on June 15, 2004
Accepted on July 7, 2004

Increased Expression of Transforming Growth Factor-1 as a Stabilizing Factor in Human Atherosclerotic Plaques

Francesco Cipollone MD^*; Maria Fazia PhD; Gabriella Mincione PhD; Annalisa Iezzi MD; Barbara Pini MD; Chiara Cuccurullo MD; Sante Ucchino MD; Francesco Spigonardo MD; Marcello Di Nisio MD; Franco Cuccurullo MD; Andrea Mezzetti MD; and Ettore Porreca MD

From the Department of Medicine and Aging, School of Medicine, and Aging Research Center, Ce.S.I. "Gabriele d’Annunzio" University Foundation, Chieti-Pescara, Italy.

^* To whom correspondence should be addressed. E-mail: fcipollone{at}unich.it.

Background and Purpose--Transforming growth factor-beta (TGF-) 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- in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques. Furthermore, inhibition of TGF- 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-1 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-1 expression by Immunocytochemistry, Western, and Northern blotting analysis. Immunocytochemistry was used to identify CD68⁺ macrophages, CD3 T lymphocytes, HLA-DR⁺ cells, and -smooth muscle cells. Procollagen and interstitial collagen content were analyzed by immunohistochemistry and Sirius Red staining, respectively.

Results--Plaque TGF-1 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-1 gene was transcriptionally active as demonstrated by increased (P<0.0001) TGF-1 protein expression in asymptomatic plaques. Immunohistochemistry showed that TGF- 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-1 in human asymptomatic lesions and provides evidence that TGF-1 may play an important role in the process of plaque stabilization.

Key words: atherosclerosis • carotid stenosis • growth factors • inflammation

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