The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factor beta1-specific receptors on promonocytic U937 cell membranes.
Among the broad variety of compounds generated via oxidative reactions in low-density lipoproteins (LDL) and subsequently found in the atherosclerotic plaque are aldehydes that are still esterified to the parent lipid, termed core aldehydes. The most represented cholesterol core aldehyde in LDL is 9-oxononanoyl cholesterol (9-ONC), an oxidation product of cholesteryl linoleate. 9-ONC, at a concentration detectable in biological material, markedly up-regulates mRNA expression and protein level of both the pro-fibrogenic and pro-apoptotic cytokine transforming growth factor beta1 (TGF-beta1) and the TGF-beta receptor type I (TbetaRI) in human U937 promonocytic cells. We also observed increased membrane presentation of TGF-beta receptor type II (TbetaRII). Experiments employing the TbetaRI inhibitor SB431542, or the TGFbeta antagonist DANFc chimera, have shown that the effect on TbetaRI is directly induced by 9-ONC, while TbetaRII up-regulation seems stimulated by its specific ligand, i.e. TGFbeta1, over-secreted meanwhile by treated cells. Increased levels of the cytokine and of its specific receptors in 9-ONC-treated cells clearly occurs through stimulation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), as demonstrated by ERK1/2 knockdown experiments using mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MEK1 and MEK2) siRNAs, or PD98059, a selective MEK1/2 inhibitor. 9-ONC might thus sustain further vascular remodeling due to atherosclerosis, not simply by stimulating synthesis of the pro-fibrogenic cytokine TGF-beta1 in vascular cells, but also and chiefly by enhancing the TGF-beta1 autocrine loop, because of the marked up-regulation of the cytokine's specific receptors TbetaRI and TbetaRII.
Gargiulo
Simona
S
Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
Gamba
Paola
P
Sottero
Barbara
B
Biasi
Fiorella
F
Chiarpotto
Elena
E
Serviddio
Gaetano
G
Vendemiale
Gianluigi
G
Poli
Giuseppe
G
Leonarduzzi
Gabriella
G
D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055017:Monocyte-Macrophage Precursor Cells / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C114702:9-oxononanoyl cholesterol; D001549:Benzamides; D004149:Dioxoles; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II