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(Circulation. 2005;111:2805-2811.)
© 2005 American Heart Association, Inc.

Vascular Medicine

High-Density Lipoproteins Induce Transforming Growth Factor-ß₂ Expression in Endothelial Cells

Giuseppe D. Norata, PhD; Elisa Callegari, BSc; Marta Marchesi, PhD; Giulia Chiesa, PhD; Per Eriksson, PhD; Alberico L. Catapano, PhD

From the Department of Pharmacological Sciences, University of Milan, Milan, Italy (G.D.N., E.C., M.M., G.C., A.L.C.); King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden (P.E.); and Centro per lo Studio, la Terapia e la Prevenzione delle Vasculopatie Periferiche, Ospedale Bassini, Cinisello Balsamo, Italy (A.L.C.).

Correspondence to Giuseppe Danilo Norata, PhD, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy. E-mail Danilo.Norata{at}unimi.it

Received May 5, 2004; revision received December 27, 2004; accepted January 11, 2005.

Background— HDL is endowed with cardiovascular protective activities. In addition to its role in reverse cholesterol transport, HDL influences different functions of endothelial cells. In the present study, we investigated in endothelial cells the genes involved in inflammation modulated by HDL.

Methods and Results— Through cDNA array analysis, transforming growth factor (TGF)-ß₂ appeared to be a gene responsive to HDL treatment in endothelial cells. Quantitative real-time polymerase chain reaction confirmed that HDL subfraction 3 selectively induces TGF-ß₂ mRNA expression and protein release, whereas TGF-ß₁ and TGF-ß₃ were not affected. This effect was mainly PI3K/Akt dependent. Lysosphingolipids present in HDL such as sphingosine 1 phosphate and sphingosylphosphorylcholine mimicked the effects of the whole HDL. These results were confirmed in vivo in transgenic mice overexpressing human apolipoprotein (apo) A-I. Compared with apoA-I–knockout mice, phospho-Akt, phospho-ERK1/2, and TGF-ß₂ expression was increased in the aorta of transgenic mice overexpressing human apoA-I. In addition, the expression of phospho-Smad2/3, the transcription factor activated by TGF-ß, is increased in transgenic mice compared with knockout mice.

Conclusions— Because TGF-ß possesses antiinflammatory properties and stabilizes the plaque, the results of the present work suggest a novel target for the antiatherosclerotic effect of HDL.

Key Words: apolipoproteins • endothelium • lipoproteins • signal transduction

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