TY - JOUR
T1 - The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factorβ1-specific receptors on promonocytic U937 cell membranes
AU - Gargiulo, Simona
AU - Gamba, Paola
AU - Sottero, Barbara
AU - Biasi, Fiorella
AU - Chiarpotto, Elena
AU - Serviddio, Gaetano
AU - Vendemiale, Gianluigi
AU - Poli, Giuseppe
AU - Leonarduzzi, Gabriella
PY - 2009
Y1 - 2009
N2 - 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 β1 (TGF-β1) and the TGF-β receptor type I (TβRI) in human U937 promonocytic cells. We also observed increased membrane presentation of TGF-β receptor type II (TβRII). Experiments employing the TβRI inhibitor SB431542, or the TGFβ antagonist DANFc chimera, have shown that the effect on TβRI is directly induced by 9-ONC, while TβRII up-regulation seems stimulated by its specific ligand, i.e. TGFβ1, 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-β1 in vascular cells, but also and chiefly by enhancing the TGF-β1 autocrine loop, because of the marked up-regulation of the cytokine's specific receptors TβRI and TβRII.
AB - 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 β1 (TGF-β1) and the TGF-β receptor type I (TβRI) in human U937 promonocytic cells. We also observed increased membrane presentation of TGF-β receptor type II (TβRII). Experiments employing the TβRI inhibitor SB431542, or the TGFβ antagonist DANFc chimera, have shown that the effect on TβRI is directly induced by 9-ONC, while TβRII up-regulation seems stimulated by its specific ligand, i.e. TGFβ1, 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-β1 in vascular cells, but also and chiefly by enhancing the TGF-β1 autocrine loop, because of the marked up-regulation of the cytokine's specific receptors TβRI and TβRII.
KW - 9-oxononanoyl cholesterol
KW - Atherosclerosis
KW - Fibrotic plaque
KW - Mitogen-activated protein kinases
KW - TGF-β1
KW - TGF-β1 receptors
UR - http://www.scopus.com/inward/record.url?scp=63749107262&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=63749107262&partnerID=8YFLogxK
U2 - 10.1111/j.1474-9726.2009.00454.x
DO - 10.1111/j.1474-9726.2009.00454.x
M3 - Article
C2 - 19302374
AN - SCOPUS:63749107262
VL - 8
SP - 77
EP - 87
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 2
ER -