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Simvastatin Reduces Endothelial Activation and Damage But Is Partially Ineffective in Inducing Endothelial Repair in Systemic Sclerosis

NICOLETTA DEL PAPA, MICHELA CORTIANA, CLAUDIO VITALI, ILARIA SILVESTRIS, WANDA MAGLIONE, DENISE P. COMINA, TIZIANO LUCCHI, and AGOSTINO CORTELEZZI

ABSTRACT.

Objective. To investigate whether statins may improve endothelial function in systemic sclerosis (SSc) by evaluating the effects of simvastatin on vasculogenesis [indicated by the expansion of circulating endothelial progenitor cells (EPC)] and the markers of vascular injury in the peripheral blood of patients with SSc.

Methods. Twenty SSc patients with normal cholesterol concentrations and 20 hypercholesterolemic subjects were allocated to receive 20 mg/day simvastatin for 12 weeks. Peripheral blood samples were collected before and 12 weeks after initiation of treatment, and 4 weeks after discontinuation. Five-parameter, 3-color flow cytometry was performed with a FacScan to enumerate EPC and mature circulating endothelial cells (CEC). Levels of soluble E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, interleukin 6, and endothelin-1 were assessed by commercial ELISA.

Results. Simvastatin treatment significantly increased EPC in the hypercholesterolemic group, but failed to improve the EPC levels in the SSc patients, mainly in patients with late disease. Baseline levels of CEC were significantly higher in SSc patients compared with controls and at the end of the treatment they were significantly decreased. Regarding other markers of endothelial activation, we found that all the cytokine levels decreased in a statistically significant manner in the treated patients.

Conclusion. Treatment with simvastatin results in rapid and significant improvement of measures of endothelial activation, suggesting a potential role of statins in the treatment of peripheral vascular disease in SSc. The lack of effect on increase of EPC confirms our previous findings of a defective endothelial stem cell recruitment in the bone marrow of SSc patients. This could indicate that the potential effectiveness of statins in SSc could mainly be ascribed to their effectiveness in modulating endothelial activation mechanisms. (J Rheumatol First Release June 1 2008)

Key Indexing Terms:

SIMVASTATIN
ENDOTHELIAL ACTIVATION
SYSTEMIC SCLEROSIS
ENDOTHELIAL PROGENITORS
VASCULOGENESIS

From the Department of Rheumatology, G. Pini Hospital, Milano; Ematologia 1, Ospedale Maggiore IRCCS, Università degli Studi Milano, Milano; Department of Internal Medicine and Rheumatology, Ospedale Villamarina, Piombino; Unità Operativa di Geriatria, Ospedale Maggiore IRCCS, Milano; and Department of Haematology, Ospedale Policlinico IRCCS, Milano, Italy.

N. Del Papa, MD, Department of Rheumatology, G. Pini Hospital; M. Cortiana, PhD, Ematologia 1, Ospedale Maggiore IRCCS, Università degli Studi Milano; C. Vitali, MD, Department of Internal Medicine and Rheumatology, Ospedale Villamarina; I. Silvestris, PhD, Ematologia 1, Ospedale Maggiore IRCCS, Università degli Studi Milano; W. Maglione, MD; D.P. Comina, MD, Department of Rheumatology, G. Pini Hospital; T. Lucchi, MD, Unità Operativa di Geriatria, Ospedale Maggiore IRCCS; A. Cortelezzi, MD, Department of Haematology, Ospedale Policlinico IRCCS.

Address reprint requests to Dr. N. Del Papa, Department of Rheumatology, G. Pini Hospital, Via Pini 9, 20122 Milano, Italy. E-mail: delpapa@gpini.it

Accepted for publication February 14, 2008.