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 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.