Oxidation as a crucial reaction for cholesterol to induce tissue degeneration: CD36 overexpression in human promonocytic cells treated with a biologically relevant oxysterol mixture.
Oxidative stress, inflammation and altered cholesterol metabolism and levels are among the pathogenetic mechanisms of cognitive impairment that may accompany aging. Within the research area of hypercholesterolemia and age-related disease processes, the molecular mechanisms of cholesterol interaction with the inflammatory cells of the macrophage lineage are yet to be elucidated. We thus investigated the effect of both non-oxidized and oxidized cholesterol on monocytic cell differentiation and foam cell formation, as it occurs within vascular lesions during progression of atherosclerosis. In vitro experiments performed on human U937 promonocytic cells showed that a biologically representative mixture of oxysterols markedly stimulated CD36 expression and synthesis. In contrast, non-oxidized cholesterol did not exert any effect on CD36 mRNA and protein levels. Furthermore, the oxysterol-induced up-regulation of CD36 appeared to be based on the subsequent activation of protein kinase Cdelta (PKCdelta), extracellular signal-regulated kinase 1/2 (ERK1/2) and peroxisome proliferator-activated receptor gamma (PPARgamma). Cells overexpressing CD36 were indeed able to actively take up oxidized low-density lipoproteins, and become foam cells. The essential role of ERK pathway and CD36 receptor in oxysterol-induced foam cell formation was proved by the prevention of the latter event when monocytic cells were incubated in the presence of MEK1/2 selective inhibitor or anti-CD36 specific antibody. These experimental findings point to cholesterol oxidation as an essential reaction for this sterol to exert cellular stress and tissue damage in age-related diseases in which inflammation represents a main driving force.
Leonarduzzi
Gabriella
G
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Gamba
Paola
P
Gargiulo
Simona
S
Sottero
Barbara
B
Kadl
Alexandra
A
Biasi
Fiorella
F
Chiarpotto
Elena
E
Leitinger
Norbert
N
Vendemiale
Gianluigi
G
Serviddio
Gaetano
G
Poli
Giuseppe
G
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D018955:CD36 Antigens / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013261:Sterols / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects
D000098:Acetophenones; D001578:Benzopyrans; D018955:CD36 Antigens; D047495:PPAR gamma; D012333:RNA, Messenger; D013261:Sterols; D002784:Cholesterol; C085746:rottlerin; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases