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Up‐regulation of the fibrogenic cytokine TGF‐β1 by oxysterols: a mechanistic link between cholesterol and atherosclerosis
Author(s) -
Leonarduzzi Gabriella,
Sevanian Alex,
Sottero Barbara,
Arkan Melek Canan,
Biasi Fiorella,
Chiarpotto Elena,
Başağa Hüveyda,
Poli Giuseppe
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0668fje
Subject(s) - transforming growth factor , oxysterol , cytokine , cholesterol , link (geometry) , chemistry , microbiology and biotechnology , medicine , biology , biochemistry , computer science , computer network
Deposition of blood cholesterol in the subendothelial space of major arteries is a main feature of the fibrotic plaque as well as the key event in the progression of atherosclerosis. However, the mechanisms by which cholesterol triggers and sustains the fibrotic degeneration of blood arteries remain undefined. The results reported here indicate that a biologically representative mixture of oxysterols, 27‐carbon products of cholesterol oxidation, rather than an individual oxysterol at the same concentration, exerts a strong profibrogenic effect when taken up by macrophages. Incubation of murine and human macrophages with such oxysterol mixture markedly promotes both expression and synthesis of one of the most potent proinflammatory and fibrogenic cytokines, transforming growth factor β1 (TGF‐β1). By contrast, no effect on TGF‐β1 expression and synthesis was found with unoxidized cholesterol. Macrophage uptake of cholesterol and conversion to foam cells is a hallmark of early atherogenesis, but it appears that cholesterol oxidation products, as well as other low‐density lipoprotein oxidation products, are required to generate a proper fibrogenic stimulus that is not fulfilled by cholesterol deposition alone.