High-density lipoproteins induce transforming growth factor-beta2 expression in endothelial cells.
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.


RESULTS
Through cDNA array analysis, transforming growth factor (TGF)-beta2 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-beta2 mRNA expression and protein release, whereas TGF-beta1 and TGF-beta3 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-beta2 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-beta, is increased in transgenic mice compared with knockout mice.


CONCLUSIONS
Because TGF-beta possesses antiinflammatory properties and stabilizes the plaque, the results of the present work suggest a novel target for the antiatherosclerotic effect of HDL.
Norata
Giuseppe D
GD
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy. Danilo.Norata@unimi.it
Callegari
Elisa
E
Marchesi
Marta
M
Chiesa
Giulia
G
Eriksson
Per
P
Catapano
Alberico L
AL
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013107:Sphingolipids / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053781:Transforming Growth Factor beta2
D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D013107:Sphingolipids; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt