The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factorβ1-specific receptors on promonocytic U937 cell membranes

Simona Gargiulo, Paola Gamba, Barbara Sottero, Fiorella Biasi, Elena Chiarpotto, Gaetano Serviddio, Gianluigi Vendemiale, Giuseppe Poli, Gabriella Leonarduzzi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)77-87
Number of pages11
JournalAging Cell
Volume8
Issue number2
DOIs
Publication statusPublished - 2009

Fingerprint

U937 Cells
Aldehydes
Cell Membrane
Transforming Growth Factors
Growth
Up-Regulation
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Cytokines
LDL Lipoproteins
Cytokine Receptors
Atherosclerotic Plaques
Mitogen-Activated Protein Kinases
Blood Vessels
Atherosclerosis
Cholesterol
9-oxononanoyl cholesterol
Ligands
Lipids
Messenger RNA

Keywords

  • 9-oxononanoyl cholesterol
  • Atherosclerosis
  • Fibrotic plaque
  • Mitogen-activated protein kinases
  • TGF-β1
  • TGF-β1 receptors

ASJC Scopus subject areas

  • Cell Biology
  • Ageing

Cite this

The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factorβ1-specific receptors on promonocytic U937 cell membranes. / Gargiulo, Simona; Gamba, Paola; Sottero, Barbara; Biasi, Fiorella; Chiarpotto, Elena; Serviddio, Gaetano; Vendemiale, Gianluigi; Poli, Giuseppe; Leonarduzzi, Gabriella.

In: Aging Cell, Vol. 8, No. 2, 2009, p. 77-87.

Research output: Contribution to journalArticle

Gargiulo, S, Gamba, P, Sottero, B, Biasi, F, Chiarpotto, E, Serviddio, G, Vendemiale, G, Poli, G & Leonarduzzi, G 2009, 'The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factorβ1-specific receptors on promonocytic U937 cell membranes', Aging Cell, vol. 8, no. 2, pp. 77-87. https://doi.org/10.1111/j.1474-9726.2009.00454.x
Gargiulo, Simona ; Gamba, Paola ; Sottero, Barbara ; Biasi, Fiorella ; Chiarpotto, Elena ; Serviddio, Gaetano ; Vendemiale, Gianluigi ; Poli, Giuseppe ; Leonarduzzi, Gabriella. / The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factorβ1-specific receptors on promonocytic U937 cell membranes. In: Aging Cell. 2009 ; Vol. 8, No. 2. pp. 77-87.
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AU - Gargiulo, Simona

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AU - Biasi, Fiorella

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AU - Serviddio, Gaetano

AU - Vendemiale, Gianluigi

AU - Poli, Giuseppe

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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.

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